Inhibitors of the interaction between MDM2 and P53

ABSTRACT

The present invention provides compounds of formula (I), their use as an inhibitor of a p53-MDM2 interaction as well as pharmaceutical compositions comprising said compounds: 
                         
wherein n, m, p, s, t, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 20 , X, Y, Q and Z have defined meanings.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/982,043, filed May 17, 2018, which is a divisional of U.S. patentapplication Ser. No. 15/398,291, filed Jan. 4, 2017, which is adivisional of U.S. patent application Ser. No. 12/678,961, filed Mar.18, 2010, now U.S. Pat. No. 9,573,933, which is a U.S. national stage ofInternational Patent Application No. PCT/EP2008/062433, filed Sep. 18,2008, which claims priority to European Patent Application No.07116889.2, filed Sep. 21, 2007, the entire disclosures of which arehereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to compounds and compositions containingsaid compounds acting as inhibitors of the interaction between MDM2 andp53, in particular modulators of the MDM2-proteasome interaction. Theinvention also provides processes for the preparation of the disclosedcompounds and compositions and methods of using them, for instance as amedicine.

p53 is a tumour suppressor protein which plays a pivotal role in theregulation of the balance between cell proliferation and cell growtharrest/apoptosis. Under normal conditions the half life of p53 is veryshort and consequently the level of p53 in cells is low. However, inresponse to cellular DNA damage or cellular stress (e.g. oncogeneactivation, telomere erosion, hypoxia), levels of p53 increase. Thisincrease in p53 levels leads to the activation of the transcription of anumber of genes which drives the cell into either growth arrest or intothe processes of apoptosis. Thus, an important function of p53 is toprevent the uncontrolled proliferation of damaged cells and thus protectthe organism from the development of cancer.

MDM2 is a key negative regulator of p53 function. It forms a negativeautoregulatory loop by binding to the amino terminal transactivationdomain of p53 and thus MDM2 both inhibits the ability of p53 to activatetranscription and targets p53 for proteolytic degradation. Under normalconditions this regulatory loop is responsible for maintaining the lowlevels of p53. However, in tumours with wild-type p53, the equilibriumconcentration of active p53 can be increased by antagonising theinteraction between MDM2 and p53. Other activities of MDM2 are alsorequired for p53 degradation, as evidenced by the accumulation ofubiquitylated p53 when phosphorylation in the central domain of HDM2 isabrogated (Blattner et al., Hypophosphorylation of Mdm2 augments p53stability. (2002) Mol. Cell. Biol., 22, 6170-6182). The association ofHDM2 with different subunits of the 26S proteasome such as S4, S5a, S6aand S6b (3^(rd) Mdm2 workshop, September 2005 in Constance, Germany)might play a key role in this process. Thus, p53 concentrations can alsobe increased by modulating the MDM2-proteasome interaction. This willresult in restoration of the p53-mediated pro-apoptotic andanti-proliferative effects in such tumour cells. MDM2 antagonists mighteven exhibit anti-proliferative effects in tumour cells that are devoidof functional p53.

This positions the HDM2 protein as an attractive target for thedevelopment of anti-cancer therapy.

MDM2 is a cellular proto-oncogene. Over-expression of MDM2 has beenobserved in a range of cancers. MDM2 is over-expressed in a variety oftumours due to gene amplification or increased transcription ortranslation. The mechanism by which MDM2 amplification promotestumourigenesis is at least in part related to its interaction with p53.In cells over-expressing MDM2 the protective function of p53 is blockedand thus cells are unable to respond to DNA damage or cellular stress byincreasing p53 levels, leading to cell growth arrest and/or apoptosis.Thus after DNA damage and/or cellular stress, cells over-expressing MDM2are free to continue to proliferate and assume a tumorigenic phenotype.Under these conditions disruption of the interaction of p53 and MDM2would release the p53 and thus allow normal signals of growth arrestand/or apoptosis to function.

MDM2 may also have separate functions in addition to inhibition of p53.The number of MDM2 substrates is rapidly expanding. For example, it hasbeen shown that MDM2 interacts directly with the pRb-regulatedtranscription factor E2F1/DP1. This interaction could be crucial for thep53-independent oncogenic activities of MDM2. A domain of E2F1 showsstriking similarity to the MDM2-binding domain of p53. Since theinteractions of MDM2 with both p53 and E2F1 locate to the same bindingsite on MDM2, it can be expected that MDM2/p53 antagonists will not onlyactivate cellular p53 but also modulate E2F1 activities, which arecommonly deregulated in tumour cells. Other key examples of MDM2substrates include p63, p73, p21^(waf1,cip1).

Also the therapeutic effectiveness of DNA damaging agents currently used(chemotherapy and radiotherapy), may be limited through the negativeregulation of p53 by MDM2. Thus if the MDM2 feed-back inhibition of p53is interrupted, an increase in functional p53 levels will increase thetherapeutic effectiveness of such agents by restoring the wild-type p53function that leads to apoptosis and/or reversing of p53-associated drugresistance. It was demonstrated that combining MDM2 inhibition andDNA-damaging treatments in vivo led to synergistic anti-tumour effects(Vousden K. H., Cell, Vol. 103, 691-694, 2000).

Thus disruption of the interaction of MDM2 and p53 offers an approachfor therapeutic intervention in tumours with wild-type or mutant p53,might even exhibit anti-proliferative effects in tumour cells that aredevoid of functional p53 and furthermore can sensitise tumorigenic cellsfor chemotherapy and radiotherapy.

BACKGROUND OF THE INVENTION

WO 2006/032631 discloses inhibitors of the interaction between MDM2 andp53, useful inter alia in treating tumours and enhancing theeffectiveness of chemotherapy and radiotherapy.

The compounds of the instant invention differ structurally from thecompounds of WO 2006/032631 by comprising an additional substituent R²⁰on the central phenyl ring.

WO 2007/107543 also discloses inhibitors of the interaction between MDM2and p53, useful inter alia in treating tumours and enhancing theeffectiveness of chemotherapy and radiotherapy.

Unexpectedly, the substantial structural modifications in the presentcompounds do not impair the activity of the present compounds. Hence,the invention provides a further useful series of effective and potentsmall molecules that inhibit the interactions between MDM2 and p53 andthat are drugable.

DESCRIPTION OF THE INVENTION

The present invention provides compounds and compositions for, andmethods of, inhibiting the interactions between MDM2 and p53 fortreating proliferative disease, including tumours and cancer.Furthermore, the compounds and compositions of the invention are usefulin enhancing the effectiveness of chemotherapy and radiotherapy.

Accordingly, in an aspect the invention provides a compound of formula(I):

including any stereochemically isomeric form thereof, wherein

m is 0, 1 or 2 and when m is 0 then a direct bond is intended;

n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended;

p is 0 or 1 and when p is 0 then a direct bond is intended;

s is 0 or 1 and when s is 0 then a direct bond is intended;

t is 0 or 1 and when t is 0 then a direct bond is intended;

X is C(═O) or CHR⁸, wherein

R⁸ is selected from hydrogen; C₁₋₆alkyl; C₃₋₇cycloalkyl; —C(═O)—NR¹⁷R¹⁸;carboxyl; arylC₁₋₆alkyloxycarbonyl; heteroaryl; heteroarylcarbonyl;heteroarylC₁₋₆alkyloxycarbonyl; piperazinylcarbonyl; pyrrolidinyl;piperidinylcarbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with asubstituent selected from hydroxy, amino, aryl and heteroaryl; C₃₋₇cycloalkyl substituted with a substituent selected from hydroxy, amino,aryl and heteroaryl; piperazinylcarbonyl substituted with a substituentselected from hydroxy, hydroxyC₁₋₆alkyl andhydroxyC₁₋₆alkyloxyC₁₋₆alkyl; pyrrolidinyl substituted withhydroxyC₁₋₆alkyl; and piperidinylcarbonyl substituted with one or twosubstituents selected from hydroxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyl(dihydroxy)C₁₋₆alkyl andC₁₋₆alkyloxy(hydroxy)C₁₋₆alkyl;

R¹⁷ and R¹⁸ are each independently selected from hydrogen, C₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, arylC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl(C₁₋₆alkyl), orhydroxyC₁₋₆alkyl(arylC₁₋₆alkyl);

is —CR⁹═C< and then the dotted line is a bond, —C(═O)—CH<, —C(═O)—N<,—CHR⁹—CH<, or —CHR⁹—N<, wherein each R⁹ is independently hydrogen orC₁₋₆alkyl, or wherein R⁹ together with one of R² or R²⁰ form a directbond;

R¹ is hydrogen; aryl; heteroaryl; C₁₋₆alkyloxycarbonyl; C₁₋₁₂alkyl; orC₁₋₁₂alkyl substituted with one or two substituents independentlyselected from hydroxy, aryl, heteroaryl, amino, C₁₋₆alkyloxy, mono- ordi(C₁₋₆alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,C₁₋₆alkylpiperazinyl, arylC₁₋₆alkylpiperazinyl,heteroarylC₁₋₆alkylpiperazinyl, C₃₋₇cycloalkyl-piperazinyl andC₃₋₇cycloalkylC₁₋₆alkylpiperazinyl;

R² and R²⁰ are each independently selected from

-   -   halo, hydroxy, cyano, nitro, carboxyl;    -   polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy;    -   C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, aryl, heteroaryl,        arylC₁₋₆alkyl, heteroaryl-C₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆alkyl,        morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,        C₁₋₆alkyloxy, aryloxy, heteroaryloxy, C₁₋₆alkylthio, arylthio,        heteroarylthio, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkylcarbonyl,        arylcarbonyl, heteroarylcarbonyl, C₁₋₆alkyloxycarbonyl,        C₃₋₇cycloalkyloxycarbonyl, aryloxycarbonyl,        heteroaryloxycarbonyl, C₁₋₆alkylcarbonyloxy,        C₃₋₇cycloalkylcarbonyloxy, arylcarbonyloxy or        heteroarylcarbonyloxy, any of said groups being optionally and        independently substituted with one or more, preferably one or        two, substituents selected from halo, hydroxy, cyano, nitro,        carboxyl, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl,        polyhaloC₁₋₆alkyl, aryl, heteroaryl, C₁₋₆alkyloxy,        C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl and        C₁₋₆alkylcarbonyloxy; and    -   —(CH₂)_(w)—(C(═O))_(y)NR²¹R²² wherein        -   w is 0, 1, 2, 3, 4, 5 or 6 and when w is 0 then a direct            bond is intended;        -   y is 0 or 1 and when y is 0 then a direct bond is intended;        -   R²¹ and R²² are each independently selected from hydrogen,            C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkylcarbonyl and            arylC₁₋₆alkylcarbonyl, any of said groups being optionally            and independently substituted with one or more, preferably            one or two, substituents selected from halo, hydroxy, amino,            mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl, polyhaloC₁₋₆alkyl,            C₁₋₆alkyloxy, aryl and heteroaryl;        -   or R²¹ and R²² together with the nitrogen to which they are            attached form morpholinyl, piperidinyl, pyrrolidinyl or            piperazinyl, any of said groups being optionally and            independently substituted with one or more, preferably one            or two, substituents selected from C₁₋₆alkyl,            polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, C₃₋₇cycloalkyl,            C₃₋₇cycloalkylC₁₋₆alkyl, arylC₁₋₆alkyl and            heteroarylC₁₋₆alkyl;

or R² and R²⁰ together with the phenyl ring to which they are attachedform a naphthalenyl group, optionally substituted with one or more,preferably one or two, substituents each independently selected fromhalo, hydroxy, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl and heteroaryl;

or R² and R²⁰ together form a bivalent radical of the formula—(CH₂)_(b)— wherein b is 3, 4 or 5, optionally substituted with one ormore, preferably one or two, substituents selected from halo, hydroxy,amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl, polyhaloC₁₋₆alkyl,C₁₋₆alkyloxy, aryl and heteroaryl;

or one of R² or R²⁰ is as defined above and the other one of R² or R²⁰together with R⁹ form a direct bond;

R³ is hydrogen; C₁₋₆alkyl; heteroaryl; C₃₋₇cycloalkyl; C₁₋₆alkylsubstituted with a substituent selected from hydroxy, amino, aryl andheteroaryl; or C₃₋₇cycloalkyl substituted with a substituent selectedfrom hydroxy, amino, aryl and heteroaryl;

R⁴ and R⁵ are each independently hydrogen, halo, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, polyhalo-C₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl, hydroxy,amino, C₂₋₆alkenyl or C₁₋₆alkyloxy; or

R⁴ and R⁵ together form a bivalent radical selected from methylenedioxyor ethylenedioxy;

R⁶ is hydrogen, C₁₋₆alkyloxycarbonyl, or C₁₋₆alkyl;

when p is 1 then R⁷ is hydrogen, arylC₁₋₆alkyl, hydroxy, orheteroarylC₁₋₆alkyl;

Z is a radical selected from

wherein

-   -   R¹⁰ or R¹¹ are each independently selected from hydrogen, halo,        hydroxy, amino, C₁₋₆alkyl, nitro, polyhaloC₁₋₆alkyl, cyano,        cyanoC₁₋₆alkyl, tetrazoloC₁₋₆alkyl, aryl, heteroaryl,        arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl, aryl(hydroxy)C₁₋₆alkyl,        heteroaryl(hydroxy)C₁₋₆alkyl, arylcarbonyl, heteroarylcarbonyl,        C₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl,        heteroarylC₁₋₆alkylcarbonyl, C₁₋₆alkyloxy,        C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkyl(hydroxy)C₁₋₆alkyl,        arylC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyloxyC₁₋₆alkyl,        C₁₋₆alkylcarbonyloxyC₁₋₆alkyl,        C₁₋₆alkyloxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl,        hydroxyC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₂₋₆alkenyl,        C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,        C₁₋₆alkylcarbonyloxy, aminocarbonyl, hydroxyC₁₋₆alkyl,        aminoC₁₋₆alkyl, hydroxycarbonyl, hydroxycarbonylC₁₋₆alkyl and        —(CH₂)_(v)—(C(═O))_(r)—(CHR¹⁹)_(u)—NR¹³R¹⁴, wherein    -   v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0 then a direct bond        is intended;    -   r is 0 or 1 and when r is 0 then a direct bond is intended;    -   u is 0, 1, 2, 3, 4, 5, or 6 and when u is 0 then a direct bond        is intended;    -   R¹⁹ is hydrogen or C₁₋₆alkyl;    -   R¹³ and R¹⁴ are each independently selected from hydrogen;        C₁₋₁₂alkyl; C₁₋₆alkylcarbonyl; C₁₋₆alkylsulfonyl;        arylC₁₋₆alkylcarbonyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkylcarbonyl;        —(CH₂)_(k)—NR¹⁵R¹⁸; C₁₋₁₂alkyl substituted with a substituent        selected from hydroxy, hydroxycarbonyl, cyano,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, aryl or heteroaryl; or        C₃₋₇cycloalkyl substituted with a substituent selected from        hydroxy, C₁₋₆alkyloxy, aryl, amino, arylC₁₋₆alkyl, heteroaryl or        heteroarylC₁₋₆alkyl; or    -   R¹³ and R¹⁴ together with the nitrogen to which they are        attached form morpholinyl, piperidinyl, pyrrolidinyl,        piperazinyl, or piperazinyl substituted with a substituent        selected from C₁₋₆alkyl, arylC₁₋₆alkyl,        arylC₁₋₆alkyloxycarbonyl, heteroarylC₁₋₆alkyl, C₃₋₇cycloalkyl        and C₃₋₇cycloalkylC₁₋₆alkyl; wherein        -   k is 0, 1, 2, 3, 4, 5, or 6 and when k is 0 then a direct            bond is intended;        -   R¹⁵ and R¹⁶ are each independently selected from hydrogen;            C₁₋₁₂alkyl; arylC₁₋₆alkyloxycarbonyl; C₃₋₇cycloalkyl;            C₁₋₁₂alkyl substituted with a substituent selected from            hydroxy, C₁₋₆alkyloxy, aryl, and heteroaryl; and            C₃₋₇cycloalkyl substituted with a substituent selected from            hydroxy, C₁₋₆alkyloxy, aryl, arylC₁₋₆alkyl, heteroaryl, and            heteroarylC₁₋₆alkyl; or        -   R¹⁵ and R¹⁸ together with the nitrogen to which they are            attached form morpholinyl, piperazinyl, or piperazinyl            substituted with C₁₋₆alkyloxycarbonyl;    -   R¹² is hydrogen; C₁₋₆alkyl; C₃₋₇cycloalkyl; C₁₋₆alkyl        substituted with a substituent selected from hydroxy, amino,        C₁₋₆alkyloxy and aryl; or C₃₋₇cycloalkyl substituted with a        substituent selected from hydroxy, amino, aryl and C₁₋₆alkyloxy;

aryl is phenyl or naphthalenyl;

-   -   each phenyl or naphthalenyl can optionally be substituted with        one, two or three substituents each independently selected from        halo, hydroxy, C₁₋₆alkyl, amino, polyhaloC₁₋₆alkyl and        C₁₋₆alkyloxy; and    -   each phenyl or naphthalenyl can optionally be substituted with a        bivalent radical selected from methylenedioxy and ethylenedioxy;

heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl,thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl;

-   -   each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl,        thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, or        tetrahydrofuranyl can optionally be substituted with one, two or        three substituents each independently selected from halo,        hydroxy, C₁₋₆alkyl, amino, polyhaloC₁₋₆alkyl, aryl,        arylC₁₋₆alkyl or C₁₋₆alkyloxy; or    -   each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl,        thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be        substituted with a bivalent radical selected from methylenedioxy        or ethylenedioxy;

an N-oxide form thereof, an addition salt thereof or a solvate thereof.

The compounds of formula (I) may also exist in their tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

A number of terms used in the foregoing definitions and hereinafter areexplained hereunder. These terms may be used as such or in compositeterms.

As used herein, halo is generic to fluoro, chloro, bromo and iodo.C₁₋₆alkyl defines straight- and branched-chain saturated hydrocarbonradicals having from 1 to 6 carbon atoms such as, e.g., methyl, ethyl,propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl,2-methyl-butyl, 2-methylpentyl and the like. C₁₋₁₂ alkyl includesC₁₋₆alkyl and the higher straight- and branched-chain homologues thereofhaving 7 to 12 carbon atoms such as, for example, heptyl, octyl, nonyl,decyl, undecyl, dodecyl and the like. HydroxyC₁₋₆alkyl refers to aC₁₋₆alkyl as defined herein, wherein one or more (e.g., one, two, threeor more) hydrogens of said C₁₋₆alkyl are replaced with a hydroxylsubstituent. PolyhaloC₁₋₆alkyl and polyhalo-C₁₋₆alkyloxy refersrespectively to a C₁₋₆alkyl or a C₁₋₆alkyloxy as defined herein, whereinone, two or more hydrogens of said C₁₋₆alkyl or C₁₋₆alkyloxy arereplaced with identical or different halo substituents; the respectiveterms polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy also encompassperhaloC₁₋₆alkyl and perhaloC₁₋₆alkyloxy, i.e., C₁₋₆alkyl andC₁₋₆alkyloxy as defined herein, wherein all hydrogens of said C₁₋₆alkylor C₁₋₆alkyloxy are replaced with identical or different halogensubstituents—for example, trihalomethyl defines methyl containing threeidentical or different halo substituents, such as, e.g.,trifluoromethyl, or for example, trihalomethyloxy defines methyloxycontaining three identical or different halo substituents, such as,e.g., trifluoromethyloxy. C₂₋₆alkenyl defines straight- andbranched-chain hydrocarbon radicals containing one or more double bonds,preferably one double bond, and having from 2 to 6 carbon atoms such as,for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, and the like. C₃₋₇cycloalkyl includes alicyclicsaturated and unsaturated hydrocarbon groups having from 3 to 7 carbonatoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and the like. PreferablyC₃₋₇cycloalkyl includes alicyclic saturated hydrocarbon groups havingfrom 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like.

The term “addition salt” comprises the salts which the compounds offormula (I) are able to form with organic or inorganic bases such asamines, alkali metal bases and earth alkaline metal bases, or quaternaryammonium bases, or with organic or inorganic acids, such as mineralacids, sulfonic acids, carboxylic acids or phosphorus containing acids.

The term “addition salt” further comprises pharmaceutically acceptablesalts, metal complexes and the salts thereof, that the compounds offormula (I) are able to form.

The term “pharmaceutically acceptable salts” means pharmaceuticallyacceptable acid or base addition salts. The pharmaceutically acceptableacid or base addition salts as mentioned hereinabove are meant tocomprise the therapeutically active non-toxic acid and non-toxic baseaddition salt forms which the compounds of formula (I) are able to form.The compounds of formula (I) which have basic properties can beconverted in their pharmaceutically acceptable acid addition salts bytreating said base form with an appropriate acid. Appropriate acidscomprise, for example, inorganic acids such as hydrohalic acids, e.g.,hydrochloric or hydrobromic acid, sulphuric, nitric, phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.,butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

The compounds of formula (I) which have acidic properties may beconverted in their pharmaceutically acceptable base addition salts bytreating said acid form with a suitable organic or inorganic base.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g., the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g., the benzathine, N-methyl-D-glucamine, hydrabamine salts,and salts with amino acids such as, for example, arginine, lysine andthe like.

Preferably, the term addition salt means a pharmaceutically acceptableacid or base addition salt.

The term “metal complexes” means a complex formed between a compound offormula (I) and one or more organic or inorganic metal salt or salts.Examples of said organic or inorganic salts comprise the halogenides,nitrates, sulfates, phosphates, acetates, trifluoroacetates,trichloroacetates, propionates, tartrates, sulfonates, e.g.,methylsulfonates, 4-methylphenylsulfonates, salicylates, benzoates andthe like of the metals of the second main group of the periodicalsystem, e.g., the magnesium or calcium salts, of the third or fourthmain group, e.g., aluminium, tin, lead, as well as the first to theeighth transition groups of the periodical system such as, for example,chromium, manganese, iron, cobalt, nickel, copper, zinc and the like.

The term “stereochemically isomeric forms of compounds of formula (I)”,as used herein, defines all possible compounds made up of the same atomsbonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereomers and/orenantiomers of the basic molecular structure of said compound. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Of special interest are those compounds of formula (I) which arestereochemically pure. Pure stereoisomeric forms of the compounds andintermediates as mentioned herein are defined as isomers substantiallyfree of other enantiomeric or diastereomeric forms of the same basicmolecular structure of said compounds or intermediates. In particular,the term “stereoisomerically pure” concerns compounds or intermediateshaving a stereoisomeric excess of at least 80% (i.e., minimum 90% of oneisomer and maximum 10% of the other possible isomers) up to astereoisomeric excess of 100% (i.e., 100% of one isomer and none of theother), more preferably, compounds or intermediates having astereoisomeric excess of 90% up to 100%, even more preferably having astereoisomeric excess of 94% up to 100% and most preferably having astereoisomeric excess of 97% up to 100%. The terms “enantiomericallypure” and “diastereomerically pure” should be understood in a similarway, but then having regard to the enantiomeric excess respectivelydiastereomeric excess of the mixture in question.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several tertiary nitrogenatoms are oxidized to the so-called N-oxide, particularly those N-oxideswherein one or more of the piperidine-, piperazine- orpyridazinyl-nitrogens are N-oxidized.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g., sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise inter alia peroxyacids such as, for example, benzenecarboperoxoic acid or halosubstituted benzenecarboperoxoic acid, e.g.,3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.,peroxoacetic acid, alkylhydroperoxides, e.g., t-butyl hydro-peroxide.Suitable solvents are, for example, water, lower alcohols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

The compounds of formula (I) may form solvates, for example, with water(i.e., hydrates) or common organic solvents e.g. alcohols. As usedherein, the term “solvate” means a physical association of the compoundsof formula (I) with one or more solvent molecules, as well as the saltsthereof. This physical association involves varying degrees of ionic andother bonding, including hydrogen bonding. In certain instances thesolvate will be capable of isolation, for example, when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. The term “solvate” is intended to encompass bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include hydrates, ethanolates, methanolates, and thelike.

Furthermore, the compounds of the present invention may be amorphous ormay have one or more crystalline polymorph forms, as such forms areintended to be included in the scope of the invention.

The invention encompasses any isotopes of atoms present in the compoundsof the invention. For example, isotopes of hydrogen include tritium anddeuterium and isotopes of carbon include ¹³C and ¹⁴C.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the N-oxide forms, the acid or base addition saltsparticularly the pharmaceutically acceptable acid or base additionsalts, the solvates and all stereoisomeric forms of said compounds offormula (I).

A first group of interesting compounds (herein referred to as group“G1”) consists of those compounds of formula (I) wherein any one or moreor all of the following restrictions apply:

-   -   a) X is C(═O) or CHR⁸, wherein        -   R⁸ is selected from hydrogen; C₁₋₆alkyl; C₃₋₇cycloalkyl;            aminocarbonyl; mono- or di(C₁₋₆alkyl)aminocarbonyl;            carboxyl; arylC₁₋₆alkyloxycarbonyl;            heteroarylC₁₋₆alkyloxycarbonyl; C₁₋₆alkyloxycarbonyl;            C₁₋₆alkyl substituted with a substituent selected from            hydroxy, amino, aryl, and heteroaryl; or C₃₋₇cycloalkyl            substituted with a substituent selected from hydroxy, amino,            aryl and heteroaryl;    -   b) R¹ is hydrogen; aryl; heteroaryl; C₁₋₁₂alkyl; or C₁₋₁₂alkyl        substituted with one or two substituents independently selected        from hydroxy, aryl, heteroaryl, amino, C₁₋₆alkyloxy, mono- or        di(C₁₋₆alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl,        piperazinyl, C₁₋₆alkylpiperazinyl, arylC₁₋₆alkylpiperazinyl,        heteroarylC₁₋₆alkylpiperazinyl, C₃₋₇cycloalkylpiperazinyl and        C₃₋₇cycloalkylC₁₋₆alkylpiperazinyl;    -   c) R³ is hydrogen; C₁₋₆alkyl; C₃₋₇cycloalkyl; C₁₋₆alkyl        substituted with a substituent selected from hydroxy, amino,        aryl, and heteroaryl; or C₃₋₇cycloalkyl substituted with a        substituent selected from hydroxy, amino, aryl and heteroaryl;    -   d) R⁴ and R⁵ are each independently hydrogen, halo, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl, hydroxy, amino, C₂₋₆alkenyl        or C₁₋₆alkyloxy; in particular R⁴ and R⁵ are each independently        hydrogen, halo, C₁₋₆alkyl, polyhaloC₁₋₆alkyl, hydroxy, amino or        C₁₋₆alkyloxy;    -   e) R⁴ and R⁵ together form a bivalent radical selected from        methylenedioxy or ethylenedioxy;    -   f) R⁶ is hydrogen or C₁₋₆alkyl;    -   g) when p is 1 then R⁷ is hydrogen, arylC₁₋₆alkyl or        heteroarylC₁₋₆alkyl;    -   h) Z is a radical selected from (a-1), (a-2), (a-3), (a-4) and        (a-5);    -   i) R¹⁰ or R¹¹ are each independently selected from hydrogen;        hydroxyl; amino; C₁₋₆alkyl; nitro; polyhaloC₁₋₆alkyl; cyano;        cyanoC₁₋₆alkyl; tetrazoloC₁₋₆alkyl; aryl; heteroaryl;        arylC₁₋₆alkyl; heteroarylC₁₋₆alkyl; aryl(hydroxy)C₁₋₆alkyl;        heteroaryl(hydroxy)C₁₋₆alkyl; arylcarbonyl; heteroarylcarbonyl;        arylC₁₋₆alkylcarbonyl; heteroarylC₁₋₆alkylcarbonyl;        C₁₋₆alkyloxy; C₁₋₆alkyloxyC₁₋₆alkyl; C₁₋₆alkyloxycarbonyl;        C₁₋₆alkylcarbonyloxy; aminocarbonyl; hydroxyC₁₋₆alkyl;        aminoC₁₋₆alkyl; hydroxycarbonyl; hydroxycarbonylC₁₋₆alkyl and        —(CH₂)_(v)—(C(═O))_(r)—(CH₂)_(u)—NR¹³R¹⁴;    -   j) R¹³ and R¹⁴ are each independently selected from hydrogen;        C₁₋₁₂alkyl; C₃₋₇cycloalkyl; —(CH₂)_(k)—NR¹⁵R¹⁶; C₁₋₁₂alkyl        substituted with a substituent selected from hydroxy,        C₁₋₆alkyloxy, aryl, and heteroaryl; or C₃₋₇cycloalkyl        substituted with a substituent selected from hydroxy,        C₁₋₆alkyloxy, aryl, arylC₁₋₆alkyl, heteroaryl and        heteroarylC₁₋₆alkyl;    -   k) R¹³ and R¹⁴ together with the nitrogen to which they are        attached form morpholinyl, piperidinyl, pyrrolidinyl,        piperazinyl, or piperazinyl substituted with a substituent        selected from C₁₋₆alkyl, arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl,        C₃₋₇cycloalkyl, and C₃₋₇cycloalkylC₁₋₆alkyl;    -   l) R¹⁵ and R¹⁶ are each independently selected from hydrogen;        C₁₋₁₂alkyl; C₃₋₇cycloalkyl; C₁₋₁₂alkyl substituted with a        substituent selected from hydroxy, C₁₋₆alkyloxy, aryl, and        heteroaryl; and C₃₋₇cycloalkyl substituted with a substituent        selected from hydroxy, C₁₋₆alkyloxy, aryl, arylC₁₋₆alkyl,        heteroaryl and heteroarylC₁₋₆alkyl; in particular R¹⁵ and R¹⁶        are each independently selected from hydrogen; C₁₋₆alkyl;        C₃₋₇cycloalkyl; C₁₋₁₂ alkyl substituted with a substituent        selected from hydroxy, C₁₋₆alkyloxy, aryl, and heteroaryl; and        C₃₋₇cycloalkyl substituted with a substituent selected from        hydroxy, C₁₋₆alkyloxy, aryl, arylC₁₋₆alkyl, heteroaryl and        heteroarylC₁₋₆alkyl;    -   m) heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl,        furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl; and each        pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl,        benzofuranyl, or tetrahydrofuranyl can optionally be substituted        with one, two or three substituents each independently selected        from halo, hydroxy, C₁₋₆alkyl, amino, polyhaloC₁₋₆alkyl and        C₁₋₆alkyloxy; and    -   n) each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl,        thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be        substituted with a bivalent radical selected from methylenedioxy        or ethylenedioxy.

A second group of interesting compounds (herein referred to as group“G2”) consists of those compounds of formula (I) wherein any one or moreor all of the following restrictions apply:

-   -   a) n is 0, 1 or 2;    -   b) p is 0;    -   c) X is C(═O) or CHR⁸, preferably CHR⁸, wherein        -   R⁸ is hydrogen, aminocarbonyl, arylC₁₋₆alkyloxycarbonyl or            C₁₋₆alkyl substituted with hydroxy;

-   -   e) R¹ is hydrogen, C₁₋₁₂alkyl, or C₁₋₁₂alkyl substituted with        heteroaryl;    -   f) R³ is hydrogen or C₁₋₆alkyl;    -   g) R⁴ and R⁵ are each independently hydrogen, halo or        C₁₋₆alkyloxy;    -   h) Z is a radical selected from (a-1), (a-2), (a-3) and (a-4);    -   i) R¹⁰ or R¹¹ are each independently selected from hydrogen,        hydroxy, amino, C₁₋₆alkyl, nitro, polyhaloC₁₋₆alkyl, cyano,        aryl, arylC₁₋₆alkyl, aryl(hydroxy)C₁₋₆alkyl, arylcarbonyl,        C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,        aminocarbonyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, hydroxycarbonyl        and —(CH₂)_(v)—(C(═O))_(r)—(CH₂)_(u)—NR¹³R¹⁴;    -   j) v is 0 or 1;    -   k) r is 0 or 1;    -   l) u is 0;    -   m) R¹³ and R¹⁴ are each independently selected from hydrogen,        C₁₋₆alkyl, —(CH₂)_(k)—NR¹⁵R¹⁶ and C₁₋₁₂alkyl substituted with        hydroxy;    -   n) R¹³ and R¹⁴ together with the nitrogen to which they are        attached can form a pyrrolidinyl;    -   o) k is 2;    -   p) R¹⁵ and R¹⁶ are each independently C₁₋₆alkyl;    -   q) aryl is phenyl or phenyl substituted with halo; and    -   r) heteroaryl is pyridinyl or indolyl.

A third group of interesting compounds (herein referred to as group“G3”) consists of those compounds of formula (I) wherein any one or moreor all of the following restrictions apply:

-   -   a) m is 0 or 2;    -   b) n is 0, 2 or 3;    -   c) p is 1;    -   d) s is 1;    -   e) t is 1;    -   f) X is C(═O);

-   -    is —C(═O)—CH<, —C(═O)—N<, —CHR⁹—CH<, or —CHR⁸—N<;    -   h) R¹ is aryl; heteroaryl; C₁₋₆alkyloxycarbonyl; C₁₋₁₂alkyl; or        C₁₋₁₂alkyl substituted with one or two substituents        independently selected from hydroxy, aryl, heteroaryl, amino,        C₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)amino, morpholinyl,        piperidinyl, pyrrolidinyl, piperazinyl, C₁₋₆alkylpiperazinyl,        arylC₁₋₆alkylpiperazinyl, heteroarylC₁₋₆alkylpiperazinyl,        C₃₋₇cycloalkylpiperazinyl and        C₃₋₇cycloalkylC₁₋₆alkylpiperazinyl;    -   i) R³ is C₁₋₆alkyl; C₃₋₇cycloalkyl; C₁₋₆alkyl substituted with a        substituent selected from hydroxy, amino, aryl, and heteroaryl;        or C₃₋₇cycloalkyl substituted with a substituent selected from        hydroxy, amino, aryl and heteroaryl;    -   j) R⁴ and R⁵ are each independently C₁₋₆alkyl,        polyhaloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl,        hydroxyl, amino or C₂₋₆alkenyl; in particular C₁₋₆alkyl,        polyhalo-C₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl, hydroxy or amino;    -   k) R⁴ and R⁵ together form a bivalent radical selected from        methylenedioxy or ethylenedioxy;    -   l) R⁶ is C₁₋₆alkyloxycarbonyl or C₁₋₆alkyl;    -   m) R⁷ is hydrogen, arylC₁₋₆alkyl, hydroxy or        heteroarylC₁₋₆alkyl; and    -   n) Z is a radical selected from (a-1), (a-3), (a-4), (a-5),        (a-6), (a-7) and (a-8).

A fourth group of interesting compounds (herein referred to as group“G4”) consists of those compounds of formula (I) wherein any one or moreor all of the following restrictions apply:

-   -   a) X is C(═O) or CHR⁸, preferably CHR⁸, wherein        -   R⁸ is hydrogen, —C(═O)—NR¹⁷R¹⁸, arylC₁₋₆alkyloxycarbonyl,            C₁₋₆alkyl substituted with hydroxy, piperazinylcarbonyl            substituted with hydroxy, hydroxyC₁₋₆alkyl,            hydroxyC₁₋₆alkyloxyC₁₋₆alkyl, pyrrolidinyl substituted with            hydroxyC₁₋₆alkyl or piperidinylcarbonyl substituted with one            or two substituents selected from hydroxy, C₁₋₆alkyl,            hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,            C₁₋₆alkyl(dihydroxy)C₁₋₆alkyl or            C₁₋₆alkyloxy(hydroxy)C₁₋₆alkyl;    -   b) R¹⁷ and R¹⁸ are each independently selected from hydrogen,        C₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, arylC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl and hydroxyC₁₋₆alkyl;

-   -    is —CR⁹═C<, —CHR⁹—CH< or —CHR⁹—N<;    -   d) R¹ is hydrogen, heteroaryl, C₁₋₆alkyloxycarbonyl, C₁₋₁₂alkyl        or C₁₋₁₂alkyl substituted with heteroaryl;    -   e) R³ is hydrogen, C₁₋₆alkyl or heteroaryl;    -   f) R⁴ and R⁵ are each independently hydrogen, halo, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl, hydroxyl, C₂₋₆alkenyl        or C₁₋₆alkyloxy; in particular hydrogen, halo, C₁₋₆alkyl, cyano,        cyanoC₁₋₆alkyl, hydroxy or C₁₋₆alkyloxy;    -   g) when p is 1 then R⁷ is arylC₁₋₆alkyl or hydroxy;    -   h) Z is a radical selected from (a-1), (a-2), (a-3), (a-4),        (a-5), (a-7), (a-8) and (a-9);    -   i) R¹⁰ or R¹¹ are each independently selected from hydrogen,        halo, hydroxy, amino, C₁₋₆alkyl, nitro, polyhaloC₁₋₆alkyl,        cyano, cyanoC₁₋₆alkyl, tetrazoloC₁₋₆alkyl, aryl, heteroaryl,        heteroarylC₁₋₆alkyl, aryl(hydroxy)C₁₋₆alkyl, arylcarbonyl,        C₁₋₆alkylcarbonyl, C₃₋₇cycloalkylcarbonyl,        C₃₋₇cycloalkyl(hydroxy)C₁₋₆alkyl, arylC₁₋₆alkyloxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyloxyC₁₋₆alkyl,        C₁₋₆alkylcarbonyloxyC₁₋₆alkyl,        C₁₋₆alkyloxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl,        hydroxyC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₂₋₆alkenyl,        C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl,        hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, hydroxycarbonyl,        hydroxycarbonyl-C₁₋₆alkyl and        —(CH₂)_(v)—(C(═O))_(r)—(CHR¹⁹)_(u)—NR¹³R¹⁴;    -   j) v is 0 or 1;    -   k) u is 0 or 1;    -   l) R¹² is hydrogen or C₁₋₆alkyl;    -   m) R¹³ and R¹⁴ are each independently selected from hydrogen;        C₁₋₁₂alkyl; C₁₋₆alkylcarbonyl; C₁₋₆alkylsulfonyl;        arylC₁₋₆alkylcarbonyl; C₃₋₇cycloalkylcarbonyl;        —(CH₂)_(k)—NR¹⁵R¹⁶; C₁₋₁₂alkyl substituted with a substituent        selected from hydroxy, hydroxycarbonyl, cyano,        C₁₋₆alkyloxycarbonyl or aryl;    -   n) R¹³ and R¹⁴ together with the nitrogen to which they are        attached form morpholinyl, pyrrolidinyl, piperazinyl, or        piperazinyl substituted with a substituent selected from        C₁₋₆alkyl or arylC₁₋₆alkyloxycarbonyl;    -   o) k is 2;    -   p) R¹⁵ and R¹⁶ are each independently selected from hydrogen,        C₁₋₁₂alkyl or arylC₁₋₆alkyloxycarbonyl; in particular hydrogen,        C₁₋₆alkyl or arylC₁₋₆alkyloxycarbonyl;    -   q) R¹⁵ and R¹⁸ together with the nitrogen to which they are        attached form morpholinyl, a piperazinyl or a piperazinyl        substituted with C₁₋₆alkyloxycarbonyl;    -   r) aryl is phenyl or phenyl substituted with halo;    -   s) heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl;        and    -   t) each pyridinyl, indolyl, oxadiazolyl or tetrazolyl can        optionally be substituted with one substituents selected from        C₁₋₆alkyl, aryl or arylC₁₋₆alkyl.

A fifth group of interesting compounds (herein referred to as group“G5”) consists of those compounds of formula (I) wherein any one or moreor all, preferably all, of the following restrictions apply:

-   -   a) m is 0;    -   b) n is 1 or 2;    -   c) p is 0;    -   d) s is 0;    -   e) t is 0;    -   f) X is CHR⁸;    -   g) R⁸ is hydrogen;

-   -    is —CR⁹═C<;    -   i) R⁹ is hydrogen or C₁₋₆alkyl;    -   j) R¹ is hydrogen;    -   k) R³ is hydrogen;    -   l) R⁴ and R⁵ are each independently hydrogen, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, C₂₋₆alkenyl or C₁₋₆alkyloxy;    -   m) R⁶ is hydrogen;    -   n) Z is a radical selected from (a-1), (a-2) and (a-4);    -   o) R¹⁰ and R¹¹ are each independently selected from hydrogen,        hydroxy or hydroxyC₁₋₆alkyl;    -   p) R² and R²⁰ are each independently selected from halo, cyano,        polyhaloC₁₋₆alkyl, C₁₋₆alkyl, morpholinyl, C₁₋₆alkyloxy,        hydroxyC₁₋₆alkyl, —NR²¹R²² wherein R²¹ is hydrogen and R²² is        C₁₋₆alkylcarbonyl; or    -   R² and R²⁰ together with the phenyl ring to which they are        attached form a naphthalenyl group, or    -   one of R² or R²⁰ is as defined above and the other one of R² or        R²⁰ together with R⁹ form a direct bond.

A sixth group of interesting compounds (herein referred to as group“G6”) consists of those compounds of formula (I) or any subgroupthereof, wherein:

X is C(═O) or CHR⁸, preferably CHR⁸, and R⁸ is hydrogen; —C(═O)—NR¹⁷R¹⁸;arylC₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with hydroxyl;piperazinylcarbonyl substituted with hydroxyl; hydroxyC₁₋₆alkyl;hydroxyC₁₋₆alkyloxyC₁₋₆alkyl; pyrrolidinyl substituted withhydroxyC₁₋₆alkyl; or piperidinylcarbonyl substituted with one or twosubstituents selected from hydroxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyl(dihydroxy)C₁₋₆alkyl orC₁₋₆alkyloxy(hydroxy)C₁₋₆alkyl;

-   -   R¹⁷ and R¹⁶ are each independently selected from hydrogen,        C₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, arylC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl or hydroxyC₁₋₆alkyl;

-   -    is —CR⁹═C<, —CHR⁹—CH< or —CHR⁹—N<;    -   R¹ is hydrogen, heteroaryl, C₁₋₆alkyloxycarbonyl, C₁₋₁₂alkyl or        C₁₋₁₂alkyl substituted with heteroaryl;    -   R³ is hydrogen, C₁₋₆alkyl or heteroaryl;    -   R⁴ and R⁵ are each independently hydrogen, halo, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, cyano, cyano-C₁₋₆alkyl, hydroxyl, C₂₋₆alkenyl        or C₁₋₆alkyloxy; in particular hydrogen, halo, C₁₋₆alkyl, cyano,        cyanoC₁₋₆alkyl, hydroxy or C₁₋₆alkyloxy;    -   when p is 1 then R⁷ is arylC₁₋₆alkyl or hydroxy;    -   Z is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5),        (a-7), (a-8) and (a-9);    -   R¹⁰ or R¹¹ are each independently selected from hydrogen; halo;        hydroxyl; amino; C₁₋₆alkyl; nitro; polyhaloC₁₋₆alkyl; cyano;        cyanoC₁₋₆alkyl; tetrazoloC₁₋₆alkyl; aryl; heteroaryl;        heteroarylC₁₋₆alkyl; aryl(hydroxy)C₁₋₆alkyl; arylcarbonyl;        C₁₋₆alkylcarbonyl; C₃₋₇cycloalkylcarbonyl;        C₃₋₇cycloalkyl(hydroxy)C₁₋₆alkyl; arylC₁₋₆alkyloxyC₁₋₆alkyl;        C₁₋₆alkyloxyC₁₋₆alkyloxyC₁₋₆alkyl;        C₁₋₆alkylcarbonyloxyC₁₋₆alkyl;        C₁₋₆alkyloxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl;        hydroxyC₁₋₆alkyloxyC₁₋₆alkyl; C₁₋₆alkyloxycarbonylC₂₋₆alkenyl;        C₁₋₆alkyloxyC₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; aminocarbonyl;        hydroxyC₁₋₆alkyl; aminoC₁₋₆alkyl; hydroxycarbonyl;        hydroxycarbonyl-C₁₋₆alkyl and        —(CH₂)_(v)—(C(═O))_(r)—(CHR¹⁹)_(u)—NR¹³R¹⁴;    -   v is 0 or 1;    -   u is 0 or 1;    -   R¹² is hydrogen or C₁₋₆alkyl;    -   R¹³ and R¹⁴ are each independently selected from hydrogen;        C₁₋₁₂alkyl; C₁₋₆alkylcarbonyl; C₁₋₆alkylsulfonyl;        arylC₁₋₆alkylcarbonyl; C₃₋₇cycloalkylcarbonyl;        —(CH₂)_(k)—NR¹⁵R¹⁶; C₁₋₁₂alkyl substituted with a substituent        selected from hydroxy, hydroxycarbonyl, cyano,        C₁₋₆alkyloxycarbonyl or aryl; or    -   R¹³ and R¹⁴ together with the nitrogen to which they are        attached form morpholinyl, pyrrolidinyl, piperazinyl or        piperazinyl substituted with a substituent selected from        C₁₋₆alkyl or arylC₁₋₆alkyloxycarbonyl;    -   k is 2;    -   R¹⁵ and R¹⁶ are each independently selected from hydrogen,        C₁₋₁₂alkyl or arylC₁₋₆alkyloxycarbonyl; in particular hydrogen,        C₁₋₆alkyl or arylC₁₋₆alkyloxycarbonyl; or    -   R¹⁵ and R¹⁶ together with the nitrogen to which they are        attached form morpholinyl; piperazinyl; or piperazinyl        substituted with C₁₋₆alkyloxycarbonyl;    -   aryl is phenyl or phenyl substituted with halo; and    -   heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and        each pyridinyl, indolyl, oxadiazolyl or tetrazolyl can        optionally be substituted with one substituent selected from        C₁₋₆alkyl, aryl or arylC₁₋₆alkyl.

A seventh group of more preferred compounds (herein referred to as group“G7”) consists of those compounds of formula (I), wherein:

m is 0; n is 1 or 2, in particular 1; p is 0; s is 0; t is 0; X is CH₂;

is —CR⁹═C< and R⁹ is hydrogen or C₁₋₆alkyl, preferably hydrogen ormethyl, more preferably hydrogen, or R⁹ together with one of R² or R²⁰form a direct bond; R¹ is hydrogen; R³ is hydrogen; and R⁶ is hydrogen.

An eight group of more preferred compounds (herein referred to as group“G8”) consists of those compounds of formula (I) or compounds of group“G7” as defined above, wherein:

-   -   R⁴ and R⁵ are each independently hydrogen, halo, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, polyhalo-C₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl,        hydroxy, amino, C₂₋₆alkenyl or C₁₋₆alkyloxy; in particular        hydrogen, halo, C₁₋₆alkyl, polyhaloC₁₋₆alkyl, cyano,        cyanoC₁₋₆alkyl, hydroxy, amino or C₁₋₆alkyloxy;    -   more preferably R⁴ and R⁵ are each independently hydrogen, halo,        C₁₋₆alkyl, hydroxyl-C₁₋₆alkylpolyhaloC₁₋₆alkyl, hydroxy, amino,        C₂₋₆alkenyl or C₁₋₆alkyloxy; in particular hydrogen, halo,        C₁₋₆alkyl, polyhaloC₁₋₆alkyl, hydroxy, amino, or C₁₋₆alkyloxy;    -   still more preferably R⁴ and R⁵ are each independently hydrogen,        halo, C₁₋₆alkyl, hydroxyl-C₁₋₆alkyl, hydroxyl, C₂₋₆alkenyl or        C₁₋₆alkyloxy; in particular hydrogen, halo, C₁₋₆alkyl, hydroxy        or C₁₋₆alkyloxy;    -   most preferably R⁴ and R⁵ are each independently hydrogen,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl or C₁₋₆alkyloxy (such        as, e.g., R⁴ and R⁵ may each independently be hydrogen, methyl        or methyloxy).

A ninth group of more preferred compounds (herein referred to as group“G9”) consists of those compounds of formula (I) or compounds of any ofgroups “G7” or “G8” as defined above, wherein:

Z is a radical selected from (a-1), (a-2), (a-3), (a-4) and (a-5);

or preferably Z is a radical selected from (a-1), (a-2) and (a-4).

A tenth group of more preferred compounds (herein referred to as group“G10”) consists of those compounds of formula (I) or compounds of any ofgroups “G7”, “G8” or “G9” as defined above, wherein:

-   -   R¹⁰ or R¹¹ are each independently selected from hydrogen, halo,        hydroxy, amino, C₁₋₆alkyl, nitro, polyhaloC₁₋₆alkyl, cyano,        cyanoC₁₋₆alkyl, tetrazoloC₁₋₆alkyl, aryl, heteroaryl,        heteroarylC₁₋₆alkyl, aryl(hydroxy)C₁₋₆alkyl, arylcarbonyl,        C₁₋₆alkylcarbonyl, C₃₋₇cycloalkylcarbonyl,        C₃₋₇cycloalkyl(hydroxy)C₁₋₆alkyl, arylC₁₋₆alkyloxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyloxyC₁₋₆alkyl,        C₁₋₆alkylcarbonyloxyC₁₋₆alkyl,        C₁₋₆alkyloxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl,        hydroxyC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₂₋₆alkenyl,        C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl,        hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, hydroxycarbonyl,        hydroxycarbonyl-C₁₋₆alkyl and        —(CH₂)_(v)—(C(═O))_(r)—(CHR¹⁹)_(u)—NR¹³R¹⁴;    -   v is 0 or 1;    -   r is 0 or 1;    -   u is 0 or 1;    -   R¹³ and R¹⁴ are each independently selected from hydrogen;        C₁₋₁₂alkyl; C₁₋₆alkylcarbonyl; C₁₋₆alkylsulfony;        arylC₁₋₆alkylcarbonyl; C₃₋₇cycloalkylcarbonyl;        —(CH₂)_(k)—NR¹⁵R¹⁶; C₁₋₁₂alkyl substituted with a substituent        selected from hydroxy, hydroxycarbonyl, cyano,        C₁₋₆alkyloxycarbonyl or aryl; or    -   R¹³ and R¹⁴ together with the nitrogen to which they are        attached form a morpholinyl, pyrrolidinyl, piperazinyl or        piperazinyl substituted with a substituent selected from        C₁₋₆alkyl or arylC₁₋₆alkyloxycarbonyl;        -   k is 2;        -   R¹⁵ and R¹⁶ are each independently selected from hydrogen,            C₁₋₁₂alkyl or arylC₁₋₆alkyloxycarbonyl; in particular            hydrogen, C₁₋₆alkyl or aryl-C₁₋₆alkyloxycarbonyl; or        -   R¹⁵ and R¹⁶ together with the nitrogen to which they are            attached form morpholinyl, piperazinyl, or piperazinyl            substituted with C₁₋₆alkyloxycarbonyl; R¹² is hydrogen or            C₁₋₆alkyl.

An eleventh group of more preferred compounds (herein referred to asgroup “G11”) consists of those compounds of group “G10” as definedabove, wherein:

R¹⁰ or R¹¹ are each independently selected from hydrogen, hydroxy,amino, C₁₋₆alkyl, nitro, polyhaloC₁₋₆alkyl, cyano, aryl, arylC₁₋₆alkyl,aryl(hydroxy)C₁₋₆alkyl, arylcarbonyl, C₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, hydroxycarbonyl and—(CH₂)_(v)—(C(═O))_(r)—(CH₂)_(u)—NR¹³R¹⁴;

-   -   v is 0 or 1;    -   r is 0 or 1;    -   u is 0;    -   R¹³ and R¹⁴ are each independently selected from hydrogen,        C₁₋₆alkyl, —(CH₂)_(k)—NR¹⁵R¹⁶ and C₁₋₁₂alkyl substituted with        hydroxy; or    -   R¹³ and R¹⁴ together with the nitrogen to which they are        attached form pyrrolidinyl;        -   k is 2;        -   R¹⁵ and R¹⁶ are each independently C₁₋₆alkyl;

R¹² is hydrogen or C₁₋₆alkyl, preferably hydrogen.

A twelfth group of more preferred compounds (herein referred to as group“G12”) consists of those compounds of group “G10” as defined above,wherein:

R¹⁰ and R¹¹ are each independently selected from hydrogen, hydroxy andhydroxyC₁₋₆alkyl; and R¹² is hydrogen or C₁₋₆alkyl, preferably hydrogen(such as, e.g., R¹⁰ and R¹¹ may each be independently selected fromhydrogen, hydroxy and hydroxymethyl; and R¹² may be hydrogen or methyl,preferably hydrogen).

A thirteenth group of more preferred compounds (herein referred to asgroup “G13”) consists of those compounds of formula (I) or compounds ofany of groups “G7”, “G8”, “G9”, “G10”, “G11” or “G12” as defined above,wherein:

aryl is phenyl or phenyl substituted with halo; and

heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and eachpyridinyl, indolyl, oxadiazolyl or tetrazolyl can optionally besubstituted with one substituent selected from C₁₋₆alkyl, aryl andarylC₁₋₆alkyl.

A fourteenth group of more preferred compounds (herein referred to asgroup “G14”) consists of those compounds of group “G13” as definedabove, wherein: aryl is phenyl or phenyl substituted with halo; and

heteroaryl is pyridinyl or indolyl.

A fifteenth group of particularly preferred compounds (herein referredto as group “G15”) consists of those compounds of formula (I) or anysubgroup thereof, wherein: m is 0; n is 1 or 2, in particular 1; p is 0;s is 0; t is 0; X is CH₂;

is —CR⁹═C< and R⁹ is hydrogen or C₁₋₆alkyl, more preferably hydrogen, orR⁹ together with one of R² or R²⁰ form a direct bond; R¹ is hydrogen; R³is hydrogen; R⁴ and R⁵ are each independently hydrogen, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₂₋₆alkenyl or C₁₋₆alkyloxy; in particular hydrogen,C₁₋₆alkyl or C₁₋₆alkyloxy; R⁸ is hydrogen; Z is a radical selected from(a-1), (a-2) and (a-4); and R¹⁰ or R¹¹ are each independently hydrogen,hydroxy or hydroxyC₁₋₆alkyl.

A sixteenth group of particularly preferred compounds (herein referredto as group “G16”) consists of those compounds of formula (I) or anysubgroup thereof, wherein:

m is 0; n is 1 or 2, in particular 1; p is 0; s is 0; t is 0; X is CH₂;

is —CR⁹═C< and R⁹ is hydrogen or methyl, or R⁹ together with one of R²or R²⁰ form a direct bond; R¹ is hydrogen; R³ is hydrogen; R⁴ and R⁵ areeach independently hydrogen, methyl or methyloxy; R⁶ is hydrogen; Z is aradical selected from (a-1), (a-2) and (a-4); and R¹⁰ or R¹¹ are eachindependently hydrogen, hydroxy or hydroxymethyl.

A seventeenth group of particularly preferred compounds (herein referredto as group “G17”) consists of those compounds of formula (I) or,whenever possible any subgroup thereof as defined hereinabove, wherein:

is —CR⁹═C< and then the dotted line is a bond, —C(═O)—CH<, —CHR⁹—CH<, or—CHR⁹—N<, wherein each R⁹ is independently hydrogen or C₁₋₆alkyl, orwherein R⁹ together with one of R² or R²⁰ form a direct bond; inparticular

is —CR⁹═C< and then the dotted line is a bond, —CHR⁹—CH<, or —CHR⁹—N<,wherein each R⁹ is independently hydrogen or C₁₋₆alkyl, or wherein R⁹together with one of R² or R²⁰ form a direct bond; more in particular

is —CR⁹═C< and then the dotted line is a bond, wherein each R⁹ isindependently hydrogen or C₁₋₆alkyl, or wherein R⁹ together with one ofR² or R²⁰ form a direct bond.

Preferably, in compounds of formula (I), and in particular in compoundsof any one of the above groups “G1” to “G17”, the substituents on thecentral phenyl ring other than R² and R²⁰ may be in the para (p-)position.

In an embodiment, when m is 1, when the substituents on the phenyl ringother than R² and R²⁰ are in the meta position, when s is 0 and t is 0;then Z may be a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6),(a-7) or (a-8).

In a preferred embodiment, in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”(the recitation “any one of the groups ‘G1’ to ‘G17’” as used throughoutthis specification encompasses a specific reference to any one or eachof the compound groups “G1”, “G2”, “G3”, “G4”, “G5”, “G6”, “G7”, “G8”,“G9”, “G10”, “G11”, “G12”, “G13”, “G14”, “G15”, “G16” or “G17” asdefined herein), R² and R²⁰ are each independently selected from halo,cyano, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl, aryl, heteroaryl,arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl, hydroxyC₁₋₆alkyl, polyhalo-C₁₋₆alkylpreferably perhaloC₁₋₆alkyl, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyloxypreferably perhaloC₁₋₆alkyloxy, arylC₁₋₆alkyloxy,heteroarylC₁₋₆alkyloxy, C₁₋₆alkylthio, arylthio preferably phenylthio,C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, morpholinyl, piperidinyl,pyrrolidinyl and piperazinyl; or R² and R²⁰ together with the centralphenyl ring form a naphthalenyl.

In another preferred embodiment, in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”, R²and R²⁰ are each independently selected from C₁₋₆alkyl, aryl,heteroaryl, arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl, hydroxyC₁₋₆alkyl,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, C₁₋₆alkyloxy, arylC₁₋₆alkyloxy,heteroarylC₁₋₆alkyloxy, C₁₋₆alkylthio, arylthio preferably phenylthio,C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamino morpholinyl, piperidinyl,pyrrolidinyl and piperazinyl, any of said groups being optionally andindependently substituted with one or more, preferably one or two,substituents selected from halo, hydroxy, cyano, amino, mono- ordi(C₁₋₆alkyl)amino, C₁₋₆alkyl, polyhaloC₁₋₆alkyl, aryl, heteroaryl andC₁₋₆alkyloxy; or R² and R²⁰ together with the central phenyl ring form anaphthalenyl.

In a particularly preferred embodiment, in compounds of formula (I), andin particular in compounds of any one of the above groups “G1” to “G17”,R² and R²⁰ are each independently selected from halo, cyano, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl preferably perhalo-C₁₋₆alkyl,C₁₋₆alkyloxy, C₁₋₆alkylcarbonylamino and morpholinyl; or R² and R²⁰together with the central phenyl ring form a naphthalenyl.

In another preferred embodiment, in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”, R²and R²⁰ are each independently selected from halo, C₁₋₆alkyl,polyhaloC₁₋₆alkyl preferably perhaloC₁₋₆alkyl, and C₁₋₆alkyloxy, or R²and R²⁰ together with the central phenyl ring form a naphthalenyl.

In another preferred embodiment, in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”, R²and R²⁰ are each independently selected from halo, C₁₋₆alkyl, andC₁₋₆alkyloxy.

In another preferred embodiment, in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”, R²and R²⁰ are each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyl, or R² and R²⁰ together with the centralphenyl ring form a naphthalenyl.

In another particularly preferred embodiment, in compounds of formula(I), and in particular in compounds of any one of the above groups “G1”to “G17”, R² and R²⁰ are each independently selected from fluoro,chloro, bromo, cyano, methyl, hydroxymethyl, trihalomethyl preferablytrifluoromethyl, methyloxy, methylcarbonylamino and morpholinyl, or R²and R²⁰ together with the central phenyl ring form a naphthalenyl.

In a further preferred embodiment, in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”, R²and R²⁰ are each independently selected from fluoro, chloro, methyl,trifluoromethyl and methyloxy, or R² and R²⁰ together with the centralphenyl ring form a naphthalenyl.

In a further preferred embodiment, in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”, R²and R²⁰ are each independently selected from fluoro, chloro, methyl andmethyloxy.

In another preferred embodiment, in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”, R²and R²⁰ are each independently selected from fluoro, chloro, bromo,methyl, methyloxy, hydroxymethyl, or R² and R²⁰ together with thecentral phenyl ring form a naphthalenyl.

In another preferred embodiment, in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”, R²and R²⁰ are each independently selected from halo, cyano,polyhaloC₁₋₆alkyl, C₁₋₆alkyl, morpholinyl, C₁₋₆alkyloxy,hydroxyl-C₁₋₆alkyl, —NR²¹R²² wherein R²¹ is hydrogen and R²² isC₁₋₆alkylcarbonyl; or R² and R²⁰ together with the phenyl ring to whichthey are attached form a naphthalenyl group, or one of R² or R²⁰ is asdefined above and the other one of R² or R²⁰ together with R⁹ form adirect bond; in particular R² and R²⁰ are each independently selectedfrom chloro, fluoro, bromo, cyano, trifluoromethyl, methyl, morpholinyl,methyloxy, hydroxymethyl, —NH—C(═O)—CH₃; or R² and R²⁰ together with thephenyl ring to which they are attached form a naphthalenyl group, or oneof R² or R²⁰ is as defined above and the other one of R² or R²⁰ togetherwith R⁹ form a direct bond.

Several preferred albeit non-limiting embodiments of compounds offormula (I), in particular of compounds of any one of the above groups“G1” to “G17”, include compounds wherein R² and R²⁰ substituentcombinations are as shown in Table 1:

TABLE 1 Combination R² R²⁰ 1 C₁₋₆alkyl C₁₋₆alkyl 2 methyl methyl 3perhaloC₁₋₆alkyl perhaloC₁₋₆alkyl 4 trifluoromethyl trifluoromethyl 5halo C₁₋₆alkyl 6 chloro methyl 7 halo halo 8 fluoro fluoro 9 chlorochloro 10 halo C₁₋₆alkyloxy 11 fluoro methyloxy 12 haloC₁₋₆alkylcarbonylamino 13 fluoro acetylamino 14 halo hydroxyC₁₋₆alkyl 15bromo hydroxymethyl 16 cyano morpholinyl 17 R² and R²⁰ together with thecentral phenyl ring form a naphthalenyl

In an embodiment, particularly interesting R², R²⁰ combinations includecombinations #1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 17 as defined inTable 1, more particularly combinations #2, 4, 6, 8, 9, 11 and 17 asdefined in Table 1.

In another embodiment, particularly interesting R², R²⁰ combinationsinclude combinations #5, 6, 7, 8, 9, 10 and 11 as defined in Table 1,more particularly combinations #10 and 11 as defined in Table 1.

In a further embodiment, particularly interesting R², R²⁰ combinationsinclude combinations #1, 2, 5, 6, 7, 8, 9, 10, 11, 14, 15 and 17 asdefined in Table 1, more particularly combinations #10 and 11 as definedin Table 1.

Thus, exemplary preferred groups of compounds consists of thosecompounds of formula (I) or any subgroup thereof, wherein:

m is 0; n is 1 or 2; p is 0; s is 0; t is 0; X is CH₂;

is —CR⁹═C< and R⁹ is hydrogen or C₁₋₆alkyl, more preferably hydrogen; R¹is hydrogen; R³ is hydrogen; R⁴ and R⁵ are each independently hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl or C₁₋₆alkyloxy; R⁶ ishydrogen; Z is a radical selected from (a-1), (a-2) and (a-4); R¹⁰ orR¹¹ are each independently hydrogen, hydroxy or hydroxyC₁₋₆alkyl; R¹² ishydrogen or C₁₋₆alkyl, preferably hydrogen; and

R² and R²⁰ are each independently selected from halo, cyano, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl preferably perhaloC₁₋₆alkyl,C₁₋₆alkyloxy, C₁₋₆alkylcarbonylamino and morpholinyl, or R² and R²⁰together with the central phenyl ring form a naphthalenyl; or one of R²or R²⁰ is as defined above and the other one of R² or R²⁰ together withR⁹ form a direct bond;

more preferably R² and R²⁰ are each independently selected from halo,C₁₋₆alkyl, polyhalo-C₁₋₆alkyl preferably perhaloC₁₋₆alkyl andC₁₋₆alkyloxy, or R² and R²⁰ together with the central phenyl ring form anaphthalenyl;

also more preferably R² and R²⁰ can be each independently selected fromhalo, C₁₋₆alkyl, and C₁₋₆alkyloxy;

as well more preferably R² and R²⁰ can be each independently selectedfrom halo, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyl, or R² and R²⁰together with the central phenyl ring to form a naphthalenyl;

even more preferably R² and R²⁰ are each independently selected fromfluoro, chloro, bromo, cyano, methyl, hydroxymethyl, trihalomethylpreferably trifluoromethyl, methyloxy, methylcarbonylamino andmorpholinyl; or R² and R²⁰ together with the central phenyl ring form anaphthalenyl; or one of R² or R²⁰ is as defined above and the other oneof R² or R²⁰ together with R⁹ form a direct bond;

still more preferably R² and R²⁰ are each independently selected fromfluoro, chloro, methyl, trifluoromethyl and methyloxy, or R² and R²⁰together with the central phenyl ring form a naphthalenyl;

also more preferably R² and R²⁰ are each independently selected fromfluoro, chloro, methyl and methyloxy;

as well more preferably R² and R²⁰ are each independently selected fromfluoro, chloro, bromo, methyl, methyloxy, hydroxymethyl, or R² and R²⁰together with the central phenyl ring form a naphthalenyl;

and also particularly preferably R² and R²⁰ may be as shown in Table 1.

Another embodiment consists of compounds of formula (I)

an N-oxide form, an addition salt, a solvate, or a stereochemicallyisomeric form thereof, wherein

m is 0, 1 or 2 and when m is 0 then a direct bond is intended;

n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended;

p is 0 or 1 and when p is 0 then a direct bond is intended;

s is 0 or 1 and when s is 0 then a direct bond is intended;

t is 0 or 1 and when t is 0 then a direct bond is intended;

X is C(═O) or CHR⁸, wherein

-   -   R⁸ is selected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,        —C(═O)—NR¹⁷R¹⁸, carboxyl, arylC₁₋₆alkyloxycarbonyl, heteroaryl,        heteroarylcarbonyl, heteroarylC₁₋₆alkyloxycarbonyl,        piperazinylcarbonyl, pyrrolidinyl, piperidinylcarbonyl,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with a substituent        selected from hydroxy, amino, aryl and heteroaryl,        C₃₋₇cycloalkyl substituted with a substituent selected from        hydroxy, amino, aryl and heteroaryl, piperazinylcarbonyl        substituted with a substituent selected from hydroxy,        hydroxyC₁₋₆alkyl and hydroxyC₁₋₆alkyloxyC₁₋₆alkyl, pyrrolidinyl        substituted with hydroxyC₁₋₆alkyl, and piperidinylcarbonyl        substituted with one or two substituents selected from hydroxy,        C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,        C₁₋₆alkyl(dihydroxy)C₁₋₆alkyl and        C₁₋₆alkyloxy(hydroxy)C₁₋₆alkyl;    -   R¹⁷ and R¹⁸ are each independently selected from hydrogen,        C₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, arylC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,        hydroxyC₁₋₆alkyl(C₁₋₆alkyl), or hydroxyC₁₋₆alkyl(arylC₁₋₆alkyl);

is —CR⁹═C< and then the dotted line is a bond, —C(═O)—CH<, —C(═O)—N<,—CHR⁹—CH<, or —CHR⁹—N<, wherein each R⁹ is independently hydrogen orC₁₋₆alkyl, or wherein R⁹ together with one of R² or R²⁰ form a directbond;

R¹ is hydrogen, aryl, heteroaryl, C₁₋₆alkyloxycarbonyl, C₁₋₁₂alkyl, orC₁₋₁₂alkyl substituted with one or two substituents independentlyselected from hydroxy, aryl, heteroaryl, amino, C₁₋₆alkyloxy, mono- ordi(C₁₋₆alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,C₁₋₆alkylpiperazinyl, arylC₁₋₆alkylpiperazinyl,heteroarylC₁₋₆alkylpiperazinyl, C₃₋₇cycloalkyl-piperazinyl andC₃₋₇cycloalkylC₁₋₆alkylpiperazinyl;

R² and R²⁰ are each independently selected from

-   -   halo, hydroxy, cyano, nitro, carboxyl;    -   polyhaloC₁₋₆alkyl, perhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,        perhaloC₁₋₆alkyloxy; C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl,        aryl, heteroaryl, arylC₁₋₆alkyl, heteroaryl-C₁₋₆alkyl,        C₃₋₇cycloalkylC₁₋₆alkyl, morpholinyl, piperidinyl, pyrrolidinyl,        piperazinyl, C₁₋₆alkyloxy, aryloxy, heteroaryloxy,        C₁₋₆alkylthio, arylthio, heteroarylthio, C₁₋₆alkylcarbonyl,        C₃₋₇cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,        C₁₋₆alkyloxycarbonyl, C₃₋₇cycloalkyloxycarbonyl,        aryloxycarbonyl, heteroaryloxycarbonyl, C₁₋₆alkylcarbonyloxy,        C₃₋₇cycloalkylcarbonyloxy, arylcarbonyloxy or        heteroarylcarbonyloxy, any of said groups being optionally        independently substituted with one or more, preferably one or        two, substituents selected from halo, hydroxy, cyano, nitro,        carboxyl, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl,        polyhaloC₁₋₆alkyl, aryl, heteroaryl, C₁₋₆alkyloxy,        C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl and        C₁₋₆alkylcarbonyloxy; and    -   —(CH₂)_(w)—(C(═O))_(y)NR²¹R²² wherein        -   w is 0, 1, 2, 3, 4, 5 or 6 and when w is 0 then a direct            bond is intended;        -   y is 0 or 1 and when y is 0 then a direct bond is intended;        -   R²¹ and R²² are each independently selected from hydrogen,            C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkylcarbonyl and            arylC₁₋₆alkylcarbonyl, any of said groups being optionally            independently substituted with one or more, preferably one            or two, substituents selected from halo, hydroxy, amino,            mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl, polyhaloC₁₋₆alkyl,            C₁₋₆alkyloxy, aryl and heteroaryl,        -   or R²¹ and R²² together with the nitrogen to which they are            attached form morpholinyl, piperidinyl, pyrrolidinyl or            piperazinyl, any of said groups being optionally            independently substituted with one or more, preferably one            or two, substituents selected from C₁₋₆alkyl,            polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, C₃₋₇cycloalkyl,            C₃₋₇cycloalkylC₁₋₆alkyl, arylC₁₋₆alkyl and            heteroarylC₁₋₆alkyl;

or R² and R²⁰ together with the phenyl ring to which they are attachedform a naphthalenyl group, optionally substituted with one or more,preferably one or two, substituents selected from halo, hydroxy, amino,mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl, polyhalo-C₁₋₆alkyl,C₁₋₆alkyloxy, aryl and heteroaryl;

or R² and R²⁰ together form a bivalent radical of the formula—(CH₂)_(b)— wherein b is 3, 4 or 5, optionally substituted with one ormore, preferably one or two, substituents selected from halo, hydroxy,amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl, polyhaloC₁₋₆alkyl,C₁₋₆alkyloxy, aryl and heteroaryl;

or one of R² or R²⁰ is as defined above and the other one of R² or R²⁰together with R⁹ form a direct bond;

R³ is hydrogen, C₁₋₆alkyl, heteroaryl, C₃₋₇cycloalkyl, C₁₋₆alkylsubstituted with a substituent selected from hydroxy, amino, aryl andheteroaryl, or C₃₋₇cycloalkyl substituted with a substituent selectedfrom hydroxy, amino, aryl and heteroaryl;

R⁴ and R⁵ are each independently hydrogen, halo, C₁₋₆alkyl,polyhaloC₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl, hydroxy, amino, orC₁₋₆alkyloxy, or

R⁴ and R⁵ together form a bivalent radical selected from methylenedioxyor ethylenedioxy;

R⁵ is hydrogen, C₁₋₆alkyloxycarbonyl, or C₁₋₆alkyl;

when p is 1 then R⁷ is hydrogen, arylC₁₋₆alkyl, hydroxy, orheteroarylC₁₋₆alkyl;

Z is a radical selected from

wherein

-   -   R¹⁰ or R¹¹ are each independently selected from hydrogen, halo,        hydroxy, amino, C₁₋₆alkyl, nitro, polyhaloC₁₋₆alkyl, cyano,        cyanoC₁₋₆alkyl, tetrazoloC₁₋₆alkyl, aryl, heteroaryl,        arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl, aryl(hydroxy)C₁₋₆alkyl,        heteroaryl(hydroxy)C₁₋₆alkyl, arylcarbonyl, heteroarylcarbonyl,        C₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl,        heteroarylC₁₋₆alkylcarbonyl, C₁₋₆alkyloxy,        C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkyl(hydroxy)C₁₋₆alkyl,        arylC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyloxyC₁₋₆alkyl,        C₁₋₆alkylcarbonyloxyC₁₋₆alkyl,        C₁₋₆alkyloxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl,        hydroxyC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₂₋₆alkenyl,        C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,        C₁₋₆alkylcarbonyloxy, aminocarbonyl, hydroxyC₁₋₆alkyl,        aminoC₁₋₆alkyl, hydroxycarbonyl, hydroxycarbonylC₁₋₆alkyl and        —(CH₂)_(v)—(C(═O))_(r)—(CHR¹⁹)_(u)—NR¹³R¹⁴,    -   wherein        -   v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0 then a direct            bond is intended;        -   r is 0 or 1 and when r is 0 then a direct bond is intended;        -   u is 0, 1, 2, 3, 4, 5, or 6 and when u is 0 then a direct            bond is intended;        -   R¹⁹ is hydrogen or C₁₋₆alkyl;        -   R¹³ and R¹⁴ are each independently selected from hydrogen,            C₁₋₁₂alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl,            arylC₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,            C₃₋₇cycloalkylcarbonyl, —(CH₂)_(k)—NR¹⁵R¹⁶, C₁₋₁₂alkyl            substituted with a substituent selected from hydroxy,            hydroxycarbonyl, cyano, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy,            aryl or heteroaryl, or C₃₋₇cycloalkyl substituted with a            substituent selected from hydroxy, C₁₋₆alkyloxy, aryl,            amino, arylC₁₋₆alkyl, heteroaryl or heteroarylC₁₋₆alkyl, or        -   R¹³ and R¹⁴ together with the nitrogen to which they are            attached form morpholinyl, piperidinyl, pyrrolidinyl,            piperazinyl, or piperazinyl substituted with a substituent            selected from C₁₋₆alkyl, arylC₁₋₆alkyl,            arylC₁₋₆alkyloxycarbonyl, heteroarylC₁₋₆alkyl,            C₃₋₇cycloalkyl and C₃₋₇cycloalkylC₁₋₆alkyl; wherein            -   k is 0, 1, 2, 3, 4, 5, or 6 and when k is 0 then a                direct bond is intended;            -   R¹⁵ and R¹⁶ are each independently selected from                hydrogen, C₁₋₆alkyl, arylC₁₋₆alkyloxycarbonyl,                C₃₋₇cycloalkyl, C₁₋₁₂alkyl substituted with a                substituent selected from hydroxy, C₁₋₆alkyloxy, aryl,                and heteroaryl, and C₃₋₇cycloalkyl substituted with a                substituent selected from hydroxy, C₁₋₆alkyloxy, aryl,                arylC₁₋₆alkyl, heteroaryl, and heteroarylC₁₋₆alkyl, or            -   R¹⁵ and R¹⁶ together with the nitrogen to which they are                attached form morpholinyl, piperazinyl, or piperazinyl                substituted with C₁₋₆alkyloxycarbonyl;    -   R¹² is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyl        substituted with a substituent selected from hydroxy, amino,        C₁₋₆alkyloxy and aryl, or C₃₋₇cycloalkyl substituted with a        substituent selected from hydroxy, amino, aryl and C₁₋₆alkyloxy;

aryl is phenyl or naphthalenyl;

-   -   each phenyl or naphthalenyl can optionally be substituted with        one, two or three substituents each independently selected from        halo, hydroxy, C₁₋₆alkyl, amino, polyhaloC₁₋₆alkyl and        C₁₋₆alkyloxy; and    -   each phenyl or naphthalenyl can optionally be substituted with a        bivalent radical selected from methylenedioxy and ethylenedioxy;

heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl,thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl;

-   -   each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl,        thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, or        tetrahydrofuranyl can optionally be substituted with one, two or        three substituents each independently selected from halo,        hydroxy, C₁₋₆alkyl, amino, polyhaloC₁₋₆alkyl, aryl,        arylC₁₋₆alkyl or C₁₋₆alkyloxy; and    -   each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl,        thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be        substituted with a bivalent radical selected from methylenedioxy        or ethylenedioxy.

Another embodiment of particularly preferred compounds consists of thosecompounds of formula (I) wherein s is 0; t is 0; m is 0; p is 0; n is 1or 2; R¹ is hydrogen; R² and R²⁰ are each independently selected fromhalo, cyano, polyhaloC₁₋₆alkyl, C₁₋₆alkyl, morpholinyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyl, —NR²¹R²² wherein R²¹ is hydrogen and R²² isC₁₋₆alkylcarbonyl; or R² and R²⁰ together with the phenyl ring to whichthey are attached form a naphthalenyl group, or one of R² or R²⁰ is asdefined above and the other one of R² or R²⁰ together with R⁹ form adirect bond; R³ is hydrogen; R⁴ and R⁵ are each independently hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl; R⁶ is hydrogen;

is —CR⁹═C< and then the dotted line is a bond; R⁹ is hydrogen orC₁₋₆alkyl; X is CH₂; Z is a radical selected from (a-1), (a-2) or (a-4);R¹⁰ and R¹¹ are each independently selected from hydrogen, hydroxy andhydroxyC₁₋₆alkyl.

It shall be appreciated that when in compounds of formula (I), and inparticular in compounds of any one of the above groups “G1” to “G17”, R²and R²⁰ together with the phenyl ring to which they are attached form anaphthalenyl group, optionally substituted as defined above, then thesubstituents

may be bound to either the same ring or to different rings of saidnaphthalenyl group.

In a preferred embodiment, R² and R²⁰ together with the phenyl ring towhich they are attached may form a naphthalenyl group, as may bedepicted by formulas (II-a) and (II-b), more preferably formula (II-a):

wherein substituents have meanings as defined above.

In another embodiment, in compounds of formula (I), and in particular incompounds of any one of the above groups “G1” to “G17”, one of R² or R²⁰is as defined herein before and the other one of R² or R²⁰ together withR⁹ form a direct bond. By means of example, compound of formula (I)wherein

is —CR⁹═C< and wherein R²⁰ together with R⁹ form a direct bond may bedepicted by the general formula (III):

wherein substituents have meanings as defined above.

Preferably, where one of R² or R²⁰ together with R⁹ form a direct bond,said direct bond may connect to a carbon of the central phenyl ringadjacent (i.e., o-position) to the carbon of the central phenyl ring towhich the —(CH₂)_(m)— group is bound.

As can be appreciated, in compounds of formula (I), and in particular incompounds of any one of the above groups “G1” to “G17”, the substituentsR² and R²⁰ may be in ortho (o-), meta (m-) or para (p-) positionsrelative to one another on the central phenyl ring.

When R² and R²⁰ together form a bivalent radical of the formula—(CH₂)_(b)— wherein b is 3, 4 or 5, optionally substituted as above,then bonds of said bivalent radical are preferably attached in ortho(o-) positions relative to one another on the central phenyl ring.

As can be appreciated, in compounds of formula (I), and in particular incompounds of any one of the above groups “G1” to “G17”, the foursubstituents on the central phenyl ring may be in various positionsrelative to one another. For example and without limitation, incompounds where substituents on the central phenyl ring other than R²and R²⁰ are in the para position, i.e., 1-, 4-, the R² and R²⁰substituents may be in positions 2- and 3-, or in positions 2- and 5-,or in positions 2- and 6-, etc.

Table 2 lists preferred albeit non-limiting examples of compounds offormula (I) that were prepared in the present invention. The followingabbreviations were used in the table: .HCl stands for hydrochloric acidsalt, mp. stands for melting point.

TABLE 2

  

In an embodiment, particularly preferred are compounds No. 2, 5, 6, 10,12, 17, 25, 29, 30, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48 and 49, even more preferably compounds No. 5, 6, 10, 17,29, 30, 31, 34, 35, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 and 49, andstill more preferably compounds No. 5, 39, 41, 42, 43 and 47; whichcompounds may achieve particularly pronounced desired biologicaleffects.

In another embodiment, particularly preferred are compounds No. 7, 9,17, 29, 30, 31, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and 49, even morepreferably compound No. 42; which compounds may achieve particularlypronounced desired biological effects.

In a further embodiment, particularly preferred are compounds No. 2, 6,8, 10, 11, 12, 13, 15, 17, 18, 19, 22, 29, 30, 31, 32, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 51, 52 and 53, even more preferablycompounds No. 38, 39, 42, 44, 45, 46, and 47; which compounds mayachieve particularly pronounced desired biological effects.

In a further embodiment, particularly preferred are the followingcompounds:

including any stereochemically isomeric form thereof;an N-oxide form thereof, an addition salt thereof or a solvate thereof.

In a further embodiment, particularly preferred are compounds No. 39,41, 42, 47, 49 and 63.

The compounds of formula (I), their N-oxides, pharmaceuticallyacceptable salts, solvates, and stereochemically isomeric forms thereofmay be prepared in conventional manner. The starting materials and someof the intermediates are known compounds and are commercially availableor may be prepared according to conventional reaction procedures asgenerally known in the art.

A number of such preparation methods will be described hereinafter inmore detail. Other methods for obtaining final compounds of formula (I)are described in the examples.

The compounds of formula (I) can be prepared by reacting an intermediateof formula (IV) with an intermediate of formula (V) wherein W is anappropriate leaving group such as, for example, halo, e.g., fluoro,chloro, bromo or iodo, or a sulfonyloxy radical such asmethylsulfonyloxy, 4-methylphenylsulfonyloxy and the like. The reactioncan be performed in a reaction-inert solvent such as, for example, analcohol, e.g., methanol, ethanol, 2-methoxy-ethanol, propanol, butanoland the like; an ether, e.g., 1, 4-dioxane, mixture hydrochloricacid/1,4-dioxane, 1,1′-oxybispropane and the like; a ketone, e.g.,4-methyl-2-pentanone; or N,N-dimethylformamide, nitrobenzene,acetonitrile, acetic acid and the like or mixtures thereof. The additionof an appropriate base such as, for example, an alkali or earth alkalinemetal carbonate or organic carbonate or organic base, e.g.,triethylamine or sodium carbonate or N,N-diisopropylethanamine, may beutilized to neutralise the acid which is liberated during the course ofthe reaction. A small amount of an appropriate metal iodide, e.g.,sodium or potassium iodide may be added to promote the reaction.Stirring may enhance the rate of the reaction. The reaction mayconveniently be carried out at a temperature ranging between roomtemperature and the reflux temperature of the reaction mixture and, ifdesired, the reaction may be carried out at an increased pressure.

The compounds of formula (I), wherein X is CH₂, herein referred to ascompounds of formula (I-a), can be prepared by reacting compounds offormula (I) wherein X is C(═O), herein referred to as compounds offormula (I-b), with lithium aluminium hydride or BH₃ in a suitablesolvent such as tetrahydrofuran.

The compounds of formula (I-a) can also be prepared by reacting anappropriate carboxaldehyde of formula (VI), with an intermediate offormula (VII), in the presence of an appropriate reagent, such as asodium borohydride, e.g., sodium tetrahydroborate or polymer supportedcyanotrihydroborate, in a suitable solvent, such as an alcohol, e.g.,methanol.

In an identical way the compounds of formula (I) wherein t is 1, hereinreferred to as compounds of formula (I-c), may be prepared by reactingan intermediate of formula (IV) with an appropriate carboxaldehyde offormula HC(═O)Z.

The compounds of formula (I), wherein s is 1, herein referred to ascompounds of formula (I-d), can be prepared by reacting an intermediateof formula (VIII) with lithium aluminium hydride in a suitable solventsuch as tetrahydrofuran.

The compounds of formula (I) wherein R⁴ is —CH₂—OH, herein referred toas compounds of formula (I-e), can be prepared by reacting anintermediate of formula (XXIV) with lithium aluminium hydride in asuitable solvent such as tetrahydrofuran.

The compounds of formula (III) can be prepared by converting anintermediate of formula (XIX) in the presence of a strong acid, forexample HCl, in a suitable solvent such as tetrahydrofuran.

The compounds of formula (III) wherein s is 0 and R³ is hydrogen, hereinreferred to as compounds of formula (III-a), can be prepared by reactingintermediates of formula (IV) wherein s is 0, R³ is hydrogen,

is —CR⁹═C< and R⁹ together with R²⁰ forms a direct bond, herein referredto as intermediates of formula (IV-c), with an intermediate of formula(V) wherein W is a suitable leaving group as defined above, in areaction-inert solvent such as, for example, an alcohol, e.g., methanol,ethanol, 2-methoxy-ethanol, propanol, butanol and the like; an ether,e.g., 1, 4-dioxane, 1,1′-oxybispropane and the like; a ketone, e.g.,4-methyl-2-pentanone; or N,N-dimethylformamide, nitrobenzene,acetonitrile, acetic acid and the like. The addition of an appropriatebase such as, for example, an alkali or earth alkaline metal carbonateor organic base, e.g., triethylamine or sodium carbonate, may beutilized to neutralise the acid which is liberated during the course ofthe reaction.

The compounds of formula (III) wherein R^(B) is hydrogen, hereinreferred to as compounds of formula (III-b), can also be prepared byFisher indole synthesis starting form intermediates of formula (XXII)and (XXIII).

The compounds of formula (I) and their intermediates may also beconverted into each other via art-known reactions or functional grouptransformations. A number of such transformations are already describedhereinabove. Other examples are hydrolysis of carboxylic esters to thecorresponding carboxylic acid or alcohol; hydrolysis of amides to thecorresponding carboxylic acids or amines; hydrolysis of nitriles to thecorresponding amides; amino groups on imidazole or phenyl may bereplaced by a hydrogen by art-known diazotation reactions and subsequentreplacement of the diazo-group by hydrogen; alcohols may be convertedinto esters and ethers; primary amines may be converted into tosecondary or tertiary amines; double bonds may be hydrogenated to thecorresponding single bond; an iodo radical on a phenyl group may beconverted in to an ester group by carbon monoxide insertion in thepresence of a suitable palladium catalyst; etc.

Intermediates of formula (IV), wherein X is CH₂, m is 0, s is 0 and R³is hydrogen, herein referred to as intermediates of formula (IV-a), canbe prepared by a nitro to amine reduction reaction starting with anintermediate of formula (IX), in the presence of a suitable catalystsuch as Raney Nickel or palladium on charcoal, and an appropriatereductant such as hydrogen, in a suitable solvent such as methanol,ethanol, toluene, tetrahydrofuran or mixtures thereof. For compoundsbearing catalytic hydrogenation sensible moieties, Pt/C optionallypoisoned with thiophene may be used. V₂O₅ may be used as an auxiliarycatalyst. Suitable solvents for this reaction are tetrahydrofuran ortoluene.

Intermediates of formula (IV), wherein X is C(═O), s is 0 and R³ ishydrogen, herein referred to as intermediates of formula (IV-b), can beprepared by reacting an intermediate of formula (X) with an intermediateof formula (XI) in the presence of appropriate coupling reagents such asN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine,monohydrochloride (EDC) and 1-hydroxy-1H-benzotriazole (HOBT). Thereaction may be performed in the presence of a base such astriethylamine, in a suitable solvent, such as, a mixture ofdichloromethane and tetrahydrofuran.

The intermediates of formula (VI) can be prepared by reactingintermediates of formula (XII) with lithium aluminium hydride in asuitable solvent such as tetrahydrofuran.

The intermediates of formula (VIII) can be prepared by reacting anintermediate of formula (XIII) with an intermediate of formula (XIV) inthe presence of 2-Chloro-1-methylpyridinium iodide and triethylamine ina suitable solvent such as acetonitrile.

The intermediates of formula (IX) can be prepared by reacting anintermediate of formula (XV) with an intermediate of formula (XVI),wherein A is an appropriate leaving group such as, for example, halo,e.g., fluoro, chloro, bromo or iodo, or C₁₋₆alkyloxy, e.g., methyloxy,in a suitable solvent such as dimethylsulfoxide or toluene, preferablyin the presence of a base such as NaHCO₃ or N,N-diisopropylethanamine,optionally at elevated temperatures such as at about 60° C.

The intermediates of formula (XIII) wherein R²⁰ represents —CH₂—OH,herein referred to as intermediates of formula (XVI-a), can be preparedby reducing an intermediate of formula (XXV) with a suitable reducingagent such as NaBH₄, in a suitable solvent such as an alcohol, e.g.methanol.

The intermediates of formula (XIII) can be prepared by converting anintermediate of formula (XVII) in the presence of sodium hydroxide andwater, in a suitable solvent, such as ethanol.

The intermediates of formula (XVII) can be prepared by reacting anintermediate of formula (XVIII), wherein A is a suitable leaving groupas defined above, with an intermediate of formula (XV), in a suitablesolvent such as diisopropylethyl amine.

Intermediates of formula (XV) wherein R¹ represents hydrogen, hereinreferred to as intermediates of formula (XV-a), can be prepared byreacting an intermediate of formula (XXVI) in the presence of a suitablecatalyst such as Raney nickel, ammonia, and a suitable solvent such asan alcohol, e.g. methanol.

Intermediates of formula (XXVI) can be prepared by reacting anintermediate of formula (XXVII) wherein C represents a suitable counterion such as e.g. iodide, with sodium cyanide in a suitable solvent suchas N,N-dimethylformamide.

Intermediates of formula (XXVI) wherein R⁴ or R⁵ representshydroxyC₁₋₆alkyl (e.g. —CH(CH₃)—OH or —C(CH₃)₂—OH) can be prepared fromthe corresponding aldehyde or ketone compound (e.g. —C(═O)H or—C(═O)—CH₃) by reaction with methyl magnesium chloride in a suitablesolvent such as tetrahydrofuran.

Intermediates of formula (XXVI) wherein R⁴ or R⁵ represents —C(═O)—CH₃can be prepared from the corresponding —CH(CH₃)—OH compound by reactionwith a suitable oxidizing reagent such as Dess Martin's reagent.

Intermediates of formula (XXVII) can be prepared from the correspondingsecondary amine by reaction with a suitable alkylating agent such asmethyl iodide, in a suitable solvent such as an alcohol, e.g. ethanol.

Intermediates of formula (IV-c) can be prepared by a nitro to aminereduction reaction starting with an intermediate of formula (XX), in thepresence of a metal catalyst such as Raney Nickel and an appropriatereductant such as hydrogen, in a suitable solvent such as methanol orethanol.

Intermediates of formula (XX) can be prepared from intermediates offormula (XXI) wherein D is an appropriate halogen leaving group such asfor example bromo or iodo, by cyclic Heck reaction in the presence of abase such as for example MgO and an organopalladium catalyst such as forexample Pd(OAc)₂, in a suitable inert polar solvent such as an alcohol,e.g., methanol, acetonitrile or DMF.

The intermediates of formula (XIX) or (XXIV) can be prepared accordingto the reaction described above for the preparation of compounds offormula (I) from intermediates of formula (IV) and (V).

Some compounds of formula (I) and some of the intermediates may have atleast one stereogenic centre in their structure. Any such stereogeniccentre may be independently present in an R or an S configuration.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Suchcompounds as prepared in the hereinabove described processes maygenerally be racemic mixtures of enantiomers or diastereoisomers, whichcan be separated from one another following art-known resolutionprocedures. For example, diastereoisomers can be separated by physicalmethods such as selective crystallization or chromatographic techniques,e.g., counter current distribution, liquid chromatography and the likemethods. Enantiomers can be obtained from racemic mixtures by firstconverting said racemic mixtures with suitable resolving agents such as,for example, chiral acids, to mixtures of diastereomeric salts orcompounds; then physically separating said mixtures of diastereomericsalts or compounds by, for example, selective crystallization,supercritical fluid chromatography or chromatographic techniques, e.g.,liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

The compounds of formula (I), pharmaceutically acceptable acid or baseaddition salts, solvates, N-oxides and stereoisomeric forms thereof havevaluable pharmacological properties in that they inhibit the interactionbetween p53 and MDM2.

The term “MDM2” (Murine Double Minute2) is used herein to mean a proteinobtained as a result of expression of the mdm2 gene. Within the meaningof this term, MDM2 encompass all proteins encoded by mdm2, mutantsthereof, alternative slice proteins thereof, and phosphorylated proteinsthereof. Additionally, as used herein, the term “MDM2” includes MDM2analogues, e.g. MDMX, also known as MDM4, and MDM2 homologues andanalogues of other animals, e.g. the human homologue HDM2 or the humananalogue HDMX.

The term “inhibiting the interaction” or “inhibitor of the interaction”is used herein to mean preventing or reducing the direct or indirectassociation of one or more molecules, peptides, proteins, enzymes orreceptors; or preventing or reducing the normal activity of one or moremolecules, peptides, proteins, enzymes, or receptors.

The term “inhibitor of the interaction of p53 with MDM2” or “p53-MDM2inhibitor” is used herein to describe an agent which increases theexpression of p53 in the assay described in C.1. This increase may becaused by, but is not limited to, one or more of the followingmechanisms of action:

-   -   inhibiting the interaction between p53 and MDM2,    -   direct association with either the MDM2 or the p53 protein,    -   interactions with upstream or downstream targets, e.g. kinases,        or enzyme activities involved in ubiquitination or SUMO        modification,    -   sequestering or transportation of MDM2 and p53 into different        cellular compartments,    -   modulation of proteins associating with MDM2, for example (but        not limited to), p63, p73, E2F-1, Rb, p21waf1 or cip1,        HIF1alpha, Foxo3A, p14ARF,    -   downregulating or interference with MDM2 expression and/or MDM2        activity, for example (but not limited to), impacting on its        cellular localisation, post-translational modification, nuclear        export, ubiquitin ligase activity or interference with binding        of MDM2 with the proteasome, modulating the MDM2-proteasome        interaction,    -   direct or indirect stabilization of the p53 protein, e.g. by        keeping it in its functional structural form, or by preventing        misfolding,    -   enhancing p53 expression or expression of p53 family members,        e.g. p63 and p73.    -   increasing p53 activity, for example by (but not limited to),        enhancing its transcriptional activity and/or    -   increasing expression of genes and proteins of the        p53-signalling pathway, for example (but not limited to)        p21waf1, cip1, MIC-1 (GDF-15), PIG-3, Bax, Puma, Noxa, and        ATF-3.

Hence, the present invention discloses the compounds of formula (I) foruse as a medicine, in particular for the treatment of cancer or relateddiseases, for inhibiting tumour growth, for inhibiting the interactionbetween MDM2 and p53, for modulating the MDM2-proteasome interaction.

Furthermore, the invention also concerns the use of a compound for themanufacture of a medicament for the treatment of a disorder mediatedthrough a p53-MDM2 interaction, wherein said compound is a compound offormula (I)

The term “treating” or “treatment” as used herein covers any treatmentof a disease and/or condition in an animal, particularly a human, andincludes: (i) inhibiting the disease and/or condition, i.e., arrestingits development; or (ii) relieving the disease and/or condition, i.e.,causing regression of the disease and/or condition. In certainembodiments, the disclosed compounds additionally prevent a diseaseand/or condition from occurring in a subject which may be predisposed tothe disease and/or condition but has not yet been diagnosed as havingit.

With the term “a disorder mediated through a p53-MDM2 interaction” ismeant any undesired or detrimental condition that results from theinteraction between the MDM2 protein and p53 or other cellular proteinsthat induce apoptosis, induce cellular death, or regulate the cellcycle.

This invention also provides a method for treating a disorder mediatedthrough a p53-MDM2 interaction by administering an effective amount of acompound of the present invention, to a subject, e.g. a mammal (and moreparticularly a human) in need of such treatment.

The compounds of the invention can have antiproliferative effects intumour cells, even if such cells are devoid of functional p53. More inparticular, the compounds of the invention can have antiproliferativeeffects in tumours with wild-type or mutant p53 and/or in tumoursoverexpressing MDM2.

Thus, this invention also provides a method for inhibiting tumour growthby administering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment.

Examples of tumours including adult and pediatric malignancies, whichmay be inhibited by the compounds of the present invention include, butare not limited to, lung cancer including small cell lung cancer andnon-small cell lung cancer (e.g. adenocarcinoma), pancreatic cancers,colon cancers (e.g. colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), oesophageal cancer, oral squamouscarcinoma, tongue carcinoma, gastric carcinoma, liver cancer,nasopharyngeal cancer, hematopoietic tumours of lymphoid lineage (e.g.acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma),non-Hodgkin's lymphoma (e.g. mantle cell lymphoma), Hodgkin's disease,myeloid leukemias (for example, acute myelogenous leukemia (AML) orchronic myelogenous leukemia (CML)), acute lymphoblastic leukemia,chronic lymphocytic leukemia (CLL), thyroid follicular cancer,myelodysplastic syndrome (MDS), tumours of mesenchymal origin, softtissue sarcomas, liposarcomas, gastrointestinal stromal sarcomas,malignant peripheral nerve sheath tumours (MPNST), Ewing sarcomas,leiomyosarcomas, mesenchymal chondrosarcomas, lymphosarcomas,fibrosarcomas, rhabdomyosarcomas, melanomas, teratocarcinomas,neuroblastomas, brain tumours, gliomas, benign tumour of the skin (e.g.keratoacanthomas), breast carcinoma (e.g. advanced breast cancer),kidney carcinoma, ovary carcinoma, cervical carcinoma, endometrialcarcinoma, bladder carcinoma, prostate cancer including the advanceddisease and hormone refractory prostate cancer, testicular cancers,osteosarcoma, head and neck cancer, epidermal carcinoma, multiplemyeloma (e.g. refractory multiple myeloma), mesothelioma. Particularcancers that can be treated with the compounds of the present inventionare breast cancer, colorectal cancer, non-small cell lung cancer, acutemyelogenous leukemia (AML).

The compounds of the present invention can also be used for thetreatment and prevention of inflammatory conditions.

Thus, this invention also provides a method for the treatment andprevention of inflammatory conditions by administering an effectiveamount of a compound of the present invention, to a subject, e.g. amammal (and more particularly a human) in need of such treatment.

The compounds of the present invention can also be used for thetreatment of autoimmune diseases and conditions. With the term“autoimmune diseases” is meant any disease in which an animal's immunesystem reacts adversely to a self-antigen. With the term “self-antigen”is meant any antigen that is normally found in the animal's body.Representative autoimmune diseases include but are not limited to:Hashimoto's thyroiditis, Grave's disease, multiple sclerosis, perniciousanemia, Addison's disease, insulin-dependent diabetes mellitus,rheumatoid arthritis, systemic lupus erythematosus (SLE or lupus),dermatomyositis, Crohn's disease, Wegener's granulomatosis, AntiGlomerular Basement Membrane Disease, Antiphospholipid Syndrome, 25Dermatitis Herpetiformis, Allergic Encephalomyelitis,Glomerulonephritis, Membranous Glomerulonephritis, Goodpasture Syndrome,Lambert-Eaton, Myasthenic Syndrome, Myasthenia Gravis, BullousPemphigoid, Polyendocrinopathies, Reiter's Disease, and Stiff-ManSyndrome.

Thus, this invention also provides a method for the treatment ofautoimmune diseases and conditions by administering an effective amountof a compound of the present invention, to a subject, e.g. a mammal (andmore particularly a human) in need of such treatment.

The compounds of the present invention can also be useful for thetreatment of diseases associated with conformational unstable ormisfolded proteins.

Examples of diseases associated with conformational unstable ormisfolded proteins include but are not limited to: cystic fibrosis(CFTR), Marfan syndrome (fibrillin), Amyotrophic lateral sclerosis(superoxide dismutase), scurvy (collagen), maple syrup urine disease(alpha-ketoacid dehydrogenase complex), osteogenesis imperfecta (typeIprocollagen pro-alpha), Creutzfeldt-Jakob disease (prion), Alzheimer'sdisease (beta-amyloid), familial amyloidosis (lysozyme), cataracts(crystallins), familial hypercholesterolemia (LDL receptor), □I-antitrypsin deficiency, Tay-Sachs disease (beta-hexosaminidase),retinitis pigmentosa (rhodopsin), and leprechaunism (insulin receptor).

Thus, this invention also provides a method for the treatment ofdiseases associated with conformational unstable or misfolded proteinsby administering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a compound of the present invention, as the activeingredient is combined in intimate admixture with a pharmaceuticallyacceptable carrier, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration. Thesepharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for administration orally, rectally,percutaneously, or by parenteral injection. For example, in preparingthe compositions in oral dosage form, any of the usual pharmaceuticalmedia may be employed, such as, for example, water, glycols, oils,alcohols and the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause a significant deleterious effect to theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on, as an ointment. It is especially advantageous toformulate the aforementioned pharmaceutical compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used in the specification and claims herein refers to physicallydiscrete units suitable as unitary dosages, each unit containing apredetermined quantity of active ingredient calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. Examples of such dosage unit forms are tablets(including scored or coated tablets), capsules, pills, powder packets,wafers, injectable solutions or suspensions, teaspoonfuls,tablespoonfuls and the like, and segregated multiples thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient, calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The compound of the invention is administered in an amount sufficient toinhibit the interaction between MDM2 and p53 or other cellular proteinsthat induce apoptosis, induce cellular death, regulate the cell cycle,regulate tumor cell migration or invasion or metastasis, in particularan amount sufficient to modulate the MDM2-proteasome interaction.

The oncogenic potential of MDM2 is not only determined by its ability tosuppress p53, but also by its ability to regulate other tumoursuppressor proteins, e.g. the retinoblastoma protein pRb and the closelyassociated E2F1 transcription factor, p63, p73.

Thus, the compound of the invention is administered in an amountsufficient to modulate the interaction between MDM2 and the E2F1transcription factors.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that a therapeutically effective amount would be from 0.005mg/kg to 100 mg/kg body weight, and in particular from 0.005 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas single, two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 0.5 to 500 mg, in particular 1 mg to 500mg, more in particular 10 mg to 500 mg of active ingredient per unitdosage form.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the compound of the present invention, and, from 1 to 99.95%by weight, more preferably from 30 to 99.9% by weight, even morepreferably from 50 to 99.9% by weight of a pharmaceutically acceptablecarrier, all percentages being based on the total weight of thecomposition.

As another aspect of the present invention, a combination of a p53-MDM2inhibitor with another anticancer agent is envisaged, especially for useas a medicine, more specifically in the treatment of cancer or relateddiseases.

For the treatment of the above conditions, the compounds of theinvention may be advantageously employed in combination with one or moreother medicinal agents, more particularly, with other anti-cancer agentsor adjuvants in cancer therapy. Examples of anti-cancer agents oradjuvants (supporting agents in the therapy) include but are not limitedto:

-   -   platinum coordination compounds for example cisplatin optionally        combined with amifostine, carboplatin or oxaliplatin;    -   taxane compounds for example paclitaxel, paclitaxel protein        bound particles (Abraxane™) or docetaxel;    -   topoisomerase I inhibitors such as camptothecin compounds for        example irinotecan, SN-38, topotecan, topotecan hcl;    -   topoisomerase II inhibitors such as anti-tumour        epipodophyllotoxins or podophyllotoxin derivatives for example        etoposide, etoposide phosphate or teniposide;    -   anti-tumour vinca alkaloids for example vinblastine, vincristine        or vinorelbine;    -   anti-tumour nucleoside derivatives for example 5-fluorouracil,        leucovorin, gemcitabine, gemcitabine hcl, capecitabine,        cladribine, fludarabine, nelarabine;    -   alkylating agents such as nitrogen mustard or nitrosourea for        example cyclophosphamide, chlorambucil, carmustine, thiotepa,        mephalan (melphalan), lomustine, altretamine, busulfan,        dacarbazine, estramustine, ifosfamide optionally in combination        with mesna, pipobroman, procarbazine, streptozocin,        telozolomide, uracil;    -   anti-tumour anthracycline derivatives for example daunorubicin,        doxorubicin optionally in combination with dexrazoxane, doxil,        idarubicin, mitoxantrone, epirubicin, epirubicin hcl,        valrubicin;    -   molecules that target the IGF-1 receptor for example        picropodophilin;    -   tetracarcin derivatives for example tetrocarcin A;    -   glucocorticoiden for example prednisone;    -   antibodies for example trastuzumab (HER2 antibody), rituximab        (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab,        pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab        tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;    -   estrogen receptor antagonists or selective estrogen receptor        modulators or inhibitors of estrogen synthesis for example        tamoxifen, fulvestrant, toremifene, droloxifene, faslodex,        raloxifene or letrozole;    -   aromatase inhibitors such as exemestane, anastrozole, letrazole,        testolactone and vorozole;    -   differentiating agents such as retinoids, vitamin D or retinoic        acid and retinoic acid metabolism blocking agents (RAMBA) for        example accutane;    -   DNA methyl transferase inhibitors for example azacytidine or        decitabine;    -   antifolates for example premetrexed disodium;    -   antibiotics for example antinomycin D, bleomycin, mitomycin C,        dactinomycin, carminomycin, daunomycin, levamisole, plicamycin,        mithramycin;    -   antimetabolites for example clofarabine, aminopterin, cytosine        arabinoside or methotrexate, azacitidine, cytarabine,        floxuridine, pentostatin, thioguanine;    -   apoptosis inducing agents and antiangiogenic agents such as        Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol,        HA 14-1, TW 37 or decanoic acid;    -   tubuline-binding agents for example combrestatin, colchicines or        nocodazole:    -   kinase inhibitors (e.g. EGFR (epithelial growth factor receptor)        inhibitors, MTKI (multi target kinase inhibitors), mTOR        inhibitors) for example flavoperidol, imatinib mesylate,        erlotinib, gefitinib, dasatinib, lapatinib, lapatinib        ditosylate, sorafenib, sunitinib, sunitinib maleate,        temsirolimus;    -   farnesyltransferase inhibitors for example tipifarnib;    -   histone deacetylase (HDAC) inhibitors for example sodium        butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide        (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A,        vorinostat;    -   Inhibitors of the ubiquitin-proteasome pathway for example        PS-341, MLN 0.41 or bortezomib;    -   Yondelis;    -   Telomerase inhibitors for example telomestatin;    -   Matrix metalloproteinase inhibitors for example batimastat,        marimastat, prinostat or metastat.    -   Recombinant interleukins for example aldesleukin, denileukin        diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon        alfa 2b    -   MAPK inhibitors    -   Retinoids for example alitretinoin, bexarotene, tretinoin    -   Arsenic trioxide    -   Asparaginase    -   Steroids for example dromostanolone propionate, megestrol        acetate, nandrolone (decanoate, phenpropionate), dexamethasone    -   Gonadotropin releasing hormone agonists or antagonists for        example abarelix, goserelin acetate, histrelin acetate,        leuprolide acetate    -   Thalidomide, lenalidomide    -   Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase,        rasburicase    -   BH3 mimetics for example ABT-737    -   MEK inhibitors for example PD98059, AZD6244, CI-1040    -   colony-stimulating factor analogs for example filgrastim,        pegfilgrastim, sargramostim; erythropoietin or analogues thereof        (e.g. darbepoetin alfa); interleukin 11; oprelvekin;        zoledronate, zoledronic acid; fentanyl; bisphosphonate;        palifermin.

As stated above, the compounds of the present invention also havetherapeutic applications in sensitising tumour cells for radiotherapyand chemotherapy.

Hence the compounds of the present invention can be used as“radiosensitizer” and/or “chemosensitizer” or can be given incombination with another “radiosensitizer” and/or “chemosensitizer”.

The term “radiosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of thecells to ionizing radiation and/or to promote the treatment of diseaseswhich are treatable with ionizing radiation.

The term “chemosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of cellsto chemotherapy and/or promote the treatment of diseases which aretreatable with chemotherapeutics.

Several mechanisms for the mode of action of radiosensitizers have beensuggested in the literature including: hypoxic cell radiosensitizers(e.g., 2- nitroimidazole compounds, and benzotriazine dioxide compounds)mimicking oxygen or alternatively behave like bioreductive agents underhypoxia; non-hypoxic cell radiosensitizers (e.g., halogenatedpyrimidines) can be analogoues of DNA bases and preferentiallyincorporate into the DNA of cancer cells and thereby promote theradiation-induced breaking of DNA molecules and/or prevent the normalDNA repair mechanisms; and various other potential mechanisms of actionhave been hypothesized for radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently employ radiosensitizers inconjunction with radiation of x-rays. Examples of x-ray activatedradiosensitizers include, but are not limited to, the following:metronidazole, misonidazole, desmethylmisonidazole, pimonidazole,etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145,nicotinamide, 5-bromodeoxyuridine (BUdR), 5- iododeoxyuridine (IUdR),bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin,and therapeutically effective analogs and derivatives of the same.

Photodynamic therapy (PDT) of cancers employs visible light as theradiation activator of the sensitizing agent. Examples of photodynamicradiosensitizers include the following, but are not limited to:hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tinetioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines,phthalocyanines, zinc phthalocyanine, and therapeutically effectiveanalogs and derivatives of the same.

Radiosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof radiosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour with or withoutadditional radiation; or other therapeutically effective compounds fortreating cancer or other diseases.

Chemosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof chemosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour or other therapeuticallyeffective compounds for treating cancer or other disease. Calciumantagonists, for example verapamil, are found useful in combination withantineoplastic agents to establish chemosensitivity in tumor cellsresistant to accepted chemotherapeutic agents and to potentiate theefficacy of such compounds in drug-sensitive malignancies.

In view of their useful pharmacological properties, the components ofthe combinations according to the invention, i.e. the one or more othermedicinal agent and the p53-MDM2 inhibitor according to the presentinvention may be formulated into various pharmaceutical forms foradministration purposes. The components may be formulated separately inindividual pharmaceutical compositions or in a unitary pharmaceuticalcomposition containing all components.

The present invention therefore also relates to a pharmaceuticalcomposition comprising the one or more other medicinal agent and thep53-MDM2 inhibitor according to the present invention together with apharmaceutical carrier.

The present invention further relates to the use of a combinationaccording to the invention in the manufacture of a pharmaceuticalcomposition for inhibiting the growth of tumour cells.

The present invention further relates to a product containing as firstactive ingredient a p53-MDM2 inhibitor according to the invention and asfurther active ingredient one or more anticancer agent, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of patients suffering from cancer.

The one or more other medicinal agents and p53-MDM2 inhibitor may beadministered simultaneously (e.g. in separate or unitary compositions)or sequentially in either order. In the latter case, the two or morecompounds will be administered within a period and in an amount andmanner that is sufficient to ensure that an advantageous or synergisticeffect is achieved. It will be appreciated that the preferred method andorder of administration and the respective dosage amounts and regimesfor each component of the combination will depend on the particularother medicinal agent and p53-MDM2 inhibitor being administered, theirroute of administration, the particular tumour being treated and theparticular host being treated. The optimum method and order ofadministration and the dosage amounts and regime can be readilydetermined by those skilled in the art using conventional methods and inview of the information set out herein.

The weight ratio of the compound according to the present invention andthe one or more other anticancer agent(s) when given as a combinationmay be determined by the person skilled in the art. Said ratio and theexact dosage and frequency of administration depends on the particularcompound according to the invention and the other anticancer agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of formula (I) and another anticancer agent may rangefrom 1/10 to 10/1, more in particular from 1/5 to 5/1, even more inparticular from 1/3 to 3/1.

The platinum coordination compound is advantageously administered in adosage of 1 to 500 mg per square meter (mg/m²) of body surface area, forexample 50 to 400 mg/m², particularly for cisplatin in a dosage of about75 mg/m² and for carboplatin in about 300 mg/m² per course of treatment.

The taxane compound is advantageously administered in a dosage of 50 to400 mg per square meter (mg/m²) of body surface area, for example 75 to250 mg/m², particularly for paclitaxel in a dosage of about 175 to 250mg/m² and for docetaxel in about 75 to 150 mg/m² per course oftreatment.

The camptothecin compound is advantageously administered in a dosage of0.1 to 400 mg per square meter (mg/m²) of body surface area, for example1 to 300 mg/m², particularly for irinotecan in a dosage of about 100 to350 mg/m² and for topotecan in about 1 to 2 mg/m² per course oftreatment.

The anti-tumour podophyllotoxin derivative is advantageouslyadministered in a dosage of 30 to 300 mg per square meter (mg/m²) ofbody surface area, for example 50 to 250 mg/m², particularly foretoposide in a dosage of about 35 to 100 mg/m² and for teniposide inabout 50 to 250 mg/m² per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in adosage of 2 to 30 mg per square meter (mg/m²) of body surface area,particularly for vinblastine in a dosage of about 3 to 12 mg/m², forvincristine in a dosage of about 1 to 2 mg/m², and for vinorelbine indosage of about 10 to 30 mg/m² per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered ina dosage of 200 to 2500 mg per square meter (mg/m²) of body surfacearea, for example 700 to 1500 mg/m², particularly for 5-FU in a dosageof 200 to 500 mg/m², for gemcitabine in a dosage of about 800 to 1200mg/m² and for capecitabine in about 1000 to 2500 mg/m² per course oftreatment.

The alkylating agents such as nitrogen mustard or nitrosourea isadvantageously administered in a dosage of 100 to 500 mg per squaremeter (mg/m²) of body surface area, for example 120 to 200 mg/m²,particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m²,for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustinein a dosage of about 150 to 200 mg/m², and for lomustine in a dosage ofabout 100 to 150 mg/m² per course of treatment.

The anti-tumour anthracycline derivative is advantageously administeredin a dosage of 10 to 75 mg per square meter (mg/m²) of body surfacearea, for example 15 to 60 mg/m², particularly for doxorubicin in adosage of about 40 to 75 mg/m², for daunorubicin in a dosage of about 25to 45 mg/m², and for idarubicin in a dosage of about 10 to 15 mg/m² percourse of treatment.

The antiestrogen agent is advantageously administered in a dosage ofabout 1 to 100 mg daily depending on the particular agent and thecondition being treated. Tamoxifen is advantageously administered orallyin a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day,continuing the therapy for sufficient time to achieve and maintain atherapeutic effect. Toremifene is advantageously administered orally ina dosage of about 60 mg once a day, continuing the therapy forsufficient time to achieve and maintain a therapeutic effect.Anastrozole is advantageously administered orally in a dosage of about 1mg once a day. Droloxifene is advantageously administered orally in adosage of about 20-100 mg once a day. Raloxifene is advantageouslyadministered orally in a dosage of about 60 mg once a day. Exemestane isadvantageously administered orally in a dosage of about 25 mg once aday.

Antibodies are advantageously administered in a dosage of about 1 to 5mg per square meter (mg/m²) of body surface area, or as known in theart, if different. Trastuzumab is advantageously administered in adosage of 1 to 5 mg per square meter (mg/m²) of body surface area,particularly 2 to 4 mg/m² per course of treatment.

These dosages may be administered for example once, twice or more percourse of treatment, which may be repeated for example every 7, 14, 21or 28 days.

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereoisomeric forms thereof can have valuablediagnostic properties in that they can be used for detecting oridentifying a p53-MDM2 interaction in a biological sample comprisingdetecting or measuring the formation of a complex between a labelledcompound and/or p53 and/or MDM2 and or other molecules, peptides,proteins, enzymes or receptors.

The detecting or identifying methods can use compounds that are labelledwith labelling agents such as radioisotopes, enzymes, fluorescentsubstances, luminous substances, etc. Examples of the radioisotopesinclude ¹²⁵I, ¹³¹I, ³H and ¹⁴C. Enzymes are usually made detectable byconjugation of an appropriate substrate which, in turn catalyses adetectable reaction. Examples thereof include, for example,beta-galactosidase, beta-glucosidase, alkaline phosphatase, peroxidaseand malate dehydrogenase, preferably horseradish peroxidase. Theluminous substances include, for example, luminol, luminol derivatives,luciferin, aequorin and luciferase.

Biological samples can be defined as body tissue or body fluids.Examples of body fluids are cerebrospinal fluid, blood, plasma, serum,urine, sputum, saliva and the like.

The following examples illustrate the present invention.

EXPERIMENTAL PART

Hereinafter, the term ‘DIPEA’ meansN-ethyl-N-(1-methylethyl)-2-propanamine, ‘K₂CO₃’ means potassiumcarbonate, ‘CH₂Cl₂’ means dichloromethane, ‘CH₃OH’ means methanol,‘MgSO₄’ means magnesium sulphate, ‘NaHCO₃’ means carbonic acidmonosodium salt, ‘DMSO’ means dimethylsulfoxide, ‘M.P.’ means meltingpoint, ‘CH₃CN’ means acetonitrile, ‘EtOAc’ means ethyl acetate, ‘DIPE’means diisopropyl ether, ‘DMF’ means N,N-dimethylformamide, ‘THF’ meanstetrahydrofuran, ‘V₂O₅’ means vanadium oxide, ‘NaBH₄’ means sodiumtetrahydroborate(-1), ‘NaCl’ means sodium chloride, ‘EtOH’ meansethanol, ‘NH₄OH’ means ammonium hydroxide. Column chromatography overSunfire means reversed-phase HPLC using C18-bonded silica stationaryphase columns Sunfire™ from Waters Corp. (Milford, Mass.)

A. Preparation of the Intermediates Example A1 a) Preparation ofIntermediate 1

A mixture of 1,2,3-trifluoro-5-nitrobenzene (0.0037 mol),1H-indole-3-ethanamine (0.0037 mol) and DIPEA (0.0189 mol) was stirredat 120° C. for 18 hours, then cooled to room temperature, poured outinto K₂CO₃ 10% aqueous solution and extracted with CH₂Cl₂/CH₃OH (few).The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated till dryness, yielding 1.3 g (>100%) of intermediate 1.

b) Preparation of Intermediate 2

A mixture of intermediate 1 (0.0037 mol) and Pd/C 10% (0.13 g) intoluene (50 ml) was hydrogenated at room temperature for 3 days underatmospheric pressure, then filtered over celite. The filtrate wasevaporated till dryness. The residue was taken up in CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness, yielding 1.2 g (>100%) of intermediate 2.

Example A2 a) Preparation of Intermediate 3

A mixture of 2-chloro-5-nitro-1,3-bis(trifluoromethyl)benzene (0.002mol), 1H-indole-3-ethanamine (0.0024 mol) and NaHCO₃ (0.0026 mol) inDMSO (4 ml) was stirred at 100° C. for 48 hours, then cooled to roomtemperature and poured out into H₂O. The precipitate was filtered,washed with diethyl ether and dried, yielding 0.41 g (49%) ofintermediate 3 (M.P.: 152° C.).

b) Preparation of Intermediate 4

A mixture of intermediate 3 (0.0008 mol) and Raney Nickel (0.36 g) inCH₃OH (10 ml) was hydrogenated at room temperature for 18 hours underatmospheric pressure, then filtered over celite. The filtrate wasevaporated till dryness. The residue was dissolved in CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness, yielding 0.32 g (96%) of intermediate 4.

Example A3 a) Preparation of Intermediate 5a

A mixture of 1,3-dichloro-2-fluoro-5-nitrobenzene (0.0048 mol),1H-indole-3-ethanamine (0.0048 mol) and NaHCO₃ (0.0057 mol) in DMSO (10ml) was stirred at 60° C. overnight, cooled to room temperature. Icewater was added. The mixture was extracted with EtOAc. The organic layerwas decanted, dried (MgSO₄), filtered off and the solvent was evaporatedtill dryness. The residue was crystallized from CH₃CN/DIPE. Theprecipitate was filtered off and dried, yielding 1.03 g (62%) ofintermediate 5a (M.P.: 98° C.).

b) Preparation of Intermediate 6a

A mixture of intermediate 5a (0.0027 mol) and Pt/C 5% (0.1 g) in V₂O₅(0.01 g), a 4% thiophene solution in DIPE (0.1 ml) and THF (20 ml) washydrogenated at room temperature for 18 hours under atmosphericpressure. The catalyst was removed by filtration. The filtrate wasevaporated till dryness, yielding 0.91 g (100%) of intermediate 6a.

c) Preparation of Intermediate 5b

A mixture of 1,3-dichloro-2-fluoro-5-nitrobenzene (0.0048 mol),1H-indole-2-methyl-3-ethanamine (0.004 mol) and NaHCO₃ (0.0048 mol) inDMSO (10 ml) was stirred at 60° C. overnight, cooled to roomtemperature. Ice water was added. The precipitate was filtered, washedwith CH₃CN and dried, yielding 0.48 g (28%) of intermediate 5b (M.P.:147° C.).

d) Preparation of Intermediate 6b

A mixture of intermediate 5b (0.0013 mol) and Pt/C 5% (0.05 g) in V₂O₅(0.005 g), a 4% thiophene solution in DIPE (0.05 ml) and THF (10 ml) washydrogenated at room temperature for 18 hours under atmosphericpressure, then filtered. The filtrate was evaporated till dryness,yielding 0.48 g (100%) of intermediate 6b.

e) Preparation of Intermediate 5c

A mixture of 1,3-dichloro-2-fluoro-5-nitrobenzene (0.0048 mol),1H-indole-6-methoxy-3-ethanamine (0.0048 mol) and NaHCO₃ (0.0057 mol) inDMSO (10 ml) was stirred at 60° C. overnight, cooled to roomtemperature. Ice water was added. The precipitate was filtered, washedwith CH₃CN and the solvent was evaporated till dryness, yielding 1.2 g(66%) of intermediate 5c (M.P.: 116° C.).

f) Preparation of Intermediate 6c

A mixture of intermediate 5c (0.0031 mol) and Pt/C 5% (0.12 g) in V₂O₅(0.012 g), a 4% thiophene solution in DIPE (0.12 ml) and THE (25 ml) washydrogenated at room temperature for 18 hours under atmosphericpressure, then filtered over celite. The filtrate was evaporated tilldryness, yielding 1.2 g (100%) of intermediate 6c.

Example A4 a) Preparation of Intermediate 7a

A mixture of 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (0.0026 mol),1H-indole-3-ethanamine (0.0026 mol) and NaHCO₃ (0.0032 mol) in DMSO (5ml) was stirred at 60° C. overnight, cooled to room temperature. Icewater was added. The precipitate was filtered off, washed with CH₃CN anddried, yielding 0.54 g (62%) of intermediate 7a (M.P.: 146° C.).

b) Preparation of Intermediate 8a

A mixture of intermediate 7a (0.0012 mol) and Pt/C 5% (0.049 g) in V₂O₅(0.005 g), a 4% thiophene solution in DIPE (0.049 ml) and THF (10 ml)was hydrogenated at room temperature for 18 hours under atmosphericpressure. The catalyst was removed by filtration. The filtrate wasevaporated till dryness, yielding 0.36 g (100%) of intermediate 8a.

c) Preparation of Intermediate 7b

A mixture of 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (0.0026 mol),1H-indole-7-methyl-3-ethanamine (0.0026 mol), NaHCO₃ (0.0032 mol) inDMSO (5 ml) was stirred at 60° C. overnight, cooled to room temperature.Ice water was added. The precipitate was filtered off, washed with CH₃CNand the solvent was evaporated till dryness, yielding 0.53 g (58%) ofintermediate 7b (M.P.: 171° C.).

d) Preparation of Intermediate 8b

A mixture of intermediate 7b (0.0014 mol) and Pt/C 5% (0.05 g) in V₂O₅(0.005 g), a 4% thiophene solution in DIPE (0.05 ml) and THF (15 ml) washydrogenated at room temperature for 18 hours under atmosphericpressure, then filtered over celite. The filtrate was evaporated tilldryness, yielding 0.49 g (100%) of intermediate 8b.

Example A5 a) Preparation of Intermediate 9

NaBH₄ (0.024 mol) was added portionwise at 5° C. to a solution of4-bromo-5-fluoro-2-nitrobenzaldehyde (0.02 mol) in CH₃OH (50 ml). Themixture was stirred at room temperature for 2 hours. Saturated NaClaqueous solution was added. The mixture was extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness, yielding 5 g (100%) of intermediate 9.

b) Preparation of Intermediate 10

A mixture of intermediate 9 (0.01 mol), 1H-indole-3-ethanamine (0.01mol) and NaHCO₃ (0.012 mol) in DMSO (25 ml) was stirred at 60° C.overnight, then cooled to room temperature. Ice and water were added.The precipitate was filtered off, washed with CH₃CN and dried, yielding1.77 g (45%) of intermediate 10.

c) Preparation of Intermediate 11

A mixture of intermediate 10 (0.0045 mol), Pt/C 5% (0.18 g) and V₂O₅(0.02 g) in a 4% thiophene solution (0.18 ml) and THE (50 ml) washydrogenated at room temperature for 48 hours under atmosphericpressure, then filtered over celite. The filtrate was evaporated tilldryness, yielding 1.7 g (100%) of intermediate 11.

Example A6 a) Preparation of Intermediate 12

A mixture of 1-fluoro-2-methyl-4-nitrobenzene (0.0103 mol),7-methyl-1H-indole-3-ethanamine (0.0103 mol) and DIPEA (0.0515 mol) wasstirred at 120° C. for 18 hours, then cooled to room temperature,diluted in CH₂Cl₂/CH₃OH (few) and washed with K₂CO₃ 10% aqueoussolution. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated till dryness. The residue (4.1 g) waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/cyclohexane 70/30; 15-35 μm). The pure fractions were collectedand the solvent was evaporated, yielding 1.45 g (45%) of intermediate12.

b) Preparation of Intermediate 13

A mixture of intermediate 12 (0.0045 mol) and Pt/C 5% (0.15 g) intoluene (40 ml) was hydrogenated at room temperature for 18 hours undera 3 bar pressure, then filtered. The filtrate was evaporated tilldryness, yielding 1.25 g (100%) of intermediate 13.

c) Preparation of Intermediate 14

A solution of intermediate 13 (0.04 mol),(7S)-4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.0044 mol),HCl/dioxane 4M (2 ml) in CH₃CN/EtOH (150 ml) was stirred at 65° C. for aweekend. K₂CO₃ 10% aqueous solution and EtOAc were added. The mixturewas extracted. The organic layer was separated, dried (MgSO₄), filteredoff and the solvent was evaporated. The residue (23 g) was purified bycolumn chromatography (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/1). The purefractions were collected and the solvent was evaporated. The residue(14.2 g, 85%) was crystallized from CH₃CN. The precipitate was filteredoff and dried, yielding 10.4 g (63%) of intermediate 14.

Example A7 a) Preparation of Intermediate 15

A mixture of 1-fluoro-2,3-dimethyl-4-nitrobenzene (0.003 mol),1H-indole-3-ethanamine (0.0036 mol) and NaHCO₃ (0.0039 mol) in DMSO (4ml) was stirred at 100° C. for 3 days, then cooled to room temperature.H₂O was added. The precipitate was filtered, washed with EtOH, then withdiethyl ether and dried. A part of this fraction was dried at 60° C. for18 hours under vacuo, yielding 0.052 g of intermediate 15 (M.P.: 178°C.).

b) Preparation of Intermediate 16

A mixture of intermediate 15 (0.0022 mol) and Raney Nickel (0.7 g) inCH₃OH/THF (90/10) (20 ml) was hydrogenated at room temperature for 3hours under atmospheric pressure, then filtered over celite. Thefiltrate was evaporated till dryness. The residue was taken up indiethyl ether. The organic layer was separated, dried (MgSO₄), filteredand the solvent was evaporated till dryness, yielding 0.64 g (100%) ofintermediate 16 (M.P.: 161° C.).

Example A8 a) Preparation of Intermediate 17

A mixture of 6-fluoro-2-(4-morpholinyl)-3-nitrobenzonitrile (0.002 mol),1H-indole-3-ethanamine (0.002 mol) and NaHCO₃ (0.0024 mol) in DMSO (5ml) was stirred at 60° C. overnight, cooled to room temperature. Icewater was added. The precipitate was filtered off, washed with CH₃CN anddried, yielding 0.64 g (82%) of intermediate 17 (M.P.: 205° C.).

b) Preparation of Intermediate 18

A mixture of intermediate 17 (0.0015 mol) and Pt/C 5% (0.06 g) in V₂O₅(0.01 g), a 4% thiophene solution in DIPE (0.06 ml) and THF (15 ml) washydrogenated at room temperature for 18 hours under atmosphericpressure. The catalyst was removed by filtration. The filtrate wasevaporated till dryness, yielding 0.61 g (100%) of intermediate 18.

Example A9 a) Preparation of Intermediate 19

A mixture of N-(4,5-difluoro-2-nitrophenyl)-acetamide (0.0023 mol),1H-indole-3-ethanamine (0.0023 mol) and NaHCO₃ (0.0028 mol) in DMSO (5ml) was stirred at 60° C. overnight, then cooled to room temperature.Ice and water were added. The precipitate was filtered off and dried,yielding 0.73 g (88%) of intermediate 19 (M.P.: 166° C.).

b) Preparation of Intermediate 20

A mixture of intermediate 19 (0.002 mol) and Raney Nickel (0.8 g) inCH₃OH (15 ml) was hydrogenated at room temperature for 4 hours underatmospheric pressure, then filtered over celite. The filtrate wasevaporated till dryness. The residue was dissolved in CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness, yielding 0.68 g (100%) of intermediate 20.

Example A10 a) Preparation of Intermediate 21

A mixture of 1,2-difluoro-3-methoxy-4-nitrobenzene (0.0074 mol),7-methoxy-1H-indole-3-ethanamine (0.0074 mol) and NaHCO₃ (0.0088 mol) inDMSO (15 ml) was stirred at 60° C. overnight, then cooled to roomtemperature. Ice and water were added. The precipitate was filtered,washed with CH₃CN and dried, yielding 2.27 g (85%) of intermediate 21(M.P.: 164° C.).

b) Preparation of Intermediate 22

A mixture of intermediate 21 (0.0058 mol), Pt/C 5% (0.21 g) and V₂O₅(0.021 g) in a 4% thiophene solution in DIPE (0.21 ml) and THF (30 ml)was hydrogenated at room temperature for 48 hours under atmosphericpressure, then filtered over celite. The filtrate was evaporated tilldryness, yielding 2.1 g (100%) of intermediate 22.

Example A11

Intermediate compounds which comprise further substituent(s) on the1H-indol-3-yl ring may be prepared analogously to the above reactions,employing a further-substituted 1H-indole-3-ethanamine, e.g.,2-methyl-1H-indole-3-ethanamine, 7-methyl-1H-indole-3-ethanamine,6-methoxy-1H-indole-3-ethanamine, or 7-methoxy-1H-indole-3-ethanamine.

Example A12 a) Preparation of Intermediate 23

A mixture of 1-methoxy-4-nitro-naphthalene (0.0005 mol) and1H-indole-3-ethanamine (0.0005 mol) in EtOH (3 ml) was stirred at 100°C. for 18 hours, then evaporated till dryness. The residue (0.4 g) waspurified by column chromatography over silica gel (eluent: CH₂Cl₂ 100).The pure fractions were collected and the solvent was evaporated,yielding 0.03 g (10%) of intermediate 23 (melting point: 211° C.).

b) Preparation of Intermediate 24

A mixture of intermediate 23 (0.002 mol) and Raney Nickel (0.7 g) inEtOH (50 ml) was hydrogenated at room temperature for 18 hours under a 3bar pressure, then filtered. The filtrate was evaporated till dryness.The residue (0.6 g) was purified by column chromatography over kromasil(eluent: CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1 to 97/3/0.3; 5 μm). The purefractions were collected and the solvent was evaporated, yielding 0.32 g(53%) of intermediate 24 (melting point: 148° C.).

Example A13 a) Preparation of Intermediate 25

Methyl iodide (0.0215 mol) was added dropwise in a solution of3-[(dimethylamino)methyl]-1H-Indole-7-carboxylic acid, methyl ester(0.0215 mol) in EtOH (50 ml). The mixture was stirred at roomtemperature for 24 hours. The precipitate was filtered off and washedwith EtOH, yielding 7.5 g of intermediate 25.

This product was used directly in the next reaction step.

b) Preparation of Intermediate 26

A mixture of intermediate 25 (0.02 mol) and sodium cyanide (0.026 mol)in DMF (75 ml) was stirred at 100° C. for 2 hours. Water was added. Theprecipitate was filtered off, yielding 2.2 g of intermediate 26.

This product was used directly in the next reaction step.

c) Preparation of Intermediate 27

Raney Nickel (37.485 mmol) was added to a solution of intermediate 26and ammonia (7M, 25 ml) under nitrogen. The mixture was hydrogenatedunder 3 bars at room temperature for 5 hours. The crude was filteredover celite and the solvent was evaporated, yielding 2.2 g ofintermediate 27.

d) Preparation of Intermediate 28

A mixture of intermediate 27 (0.00504 mol), 2,3 difluoro-6-nitroanisole(0.00504 mol) and sodium hydrogencarbonate (0.00605 mol) in DMSO (110ml) was heated at 60° C. overnight. The mixture was cooled to roomtemperature, then ice-water was added and the precipitate was filteredoff, washed with CH₃CN and dried, yielding 0.860 g of intermediate 28.

e) Preparation of Intermediate 29

A mixture of intermediate 28 (0.0022 mol) and Raney Nickel (0.0147 mol)in CH₃OH (25 ml) was hydrogenated at room temperature under atmosphericpressure of H₂ for a week-end. The catalyst was removed by filtrationand the filtrate was evaporated to dryness. The residue was dissolvedwith CH₂Cl₂, the organic layer was dried over MgSO₄, filtered andevaporated to dryness, yielding 0.6 g of intermediate 29.

This product was used directly in the next reaction step.

f) Preparation of Intermediate 30

A mixture of intermediate 29 (0.00168 mol),4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.00168 mol) andhydrogen chloride in dioxane 4M (0.000336 mol) in a solution ofCH₃CN/EtOH (25 ml) was prepared. The mixture was stirred at 65° C.overnight. K₂CO₃ 10% aqueous solution was added and the organic layerwas extracted with CH₂Cl₂, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (0.9 g) was purified by column chromatographyover silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH gradient 97/3/0.5; 90 g 15-40μm). The pure fractions were collected and the solvent was evaporated.The residue was crystallized in CH₃OH, yielding 0.160 g of intermediate30.

Example A14 a) Preparation of Intermediate 31

3-[(dimethylamino)methyl]-1H-Indole-7-carboxaldehyde (0.13 mol),iodomethane (0.14 mol) in EtOH (300 ml) were stirred at room temperaturefor 2 days. The precipitate was filtered off and dried, yielding 47 g ofintermediate 31.

b) Preparation of Intermediate 32

Intermediate 31 (136.5 mmol), sodium cyanide (177.5 mmol) in DMF (400ml) were stirred at room temperature for 2 hours. Water was added, thereaction mixture was extracted with EtOAc. The organic layer wasseparated, dried over MgSO₄, filtered and evaporated. The residue waspurified by high-performance liquid chromatography (Irregular SiOH 20-45μm 1000 g MATREX/Mobile phase:cyclohexane 70% ETOAc 30%). The purefractions were collected and the solvent was evaporated, yielding 11.8 gof intermediate 32.

c) Preparation of Intermediate 33

Methylmagnesium chloride (0.07 mol) was added dropwise to a solution ofintermediate 32 (0.022 mol) in THF (50 ml). NH₄Cl 10% aqueous solutionand EtOAc were added. The reaction mixture was extracted, the organiclayer was separated, dried over MgSO₄, filtered and evaporated. Theresidue (2.9 g) was purified by high-performance liquid chromatography(Irregular SiOH 20-45 μm 450 g MATREX/Mobile phase:cyclohexane 60% EtOAc40%). The pure fractions were collected and the solvent was evaporated,yielding 2 g of intermediate 33.

d) Preparation of Intermediate 34

Dess-Martin periodinane (24.9 ml) was added dropwise at room temperatureto a solution of intermediate 33 (10 mmol) in CH₂Cl₂ (20 ml). Thereaction mixture was stirred at room temperature for 1 hour, then pouredout into ice water, filtered over celite and the filtrate was extractedwith CH₂Cl₂. The organic layer was separated, dried over MgSO₄, filteredand the solvent was evaporated. The residue (2.8 g) was purified bycolumn chromatography over silica gel (eluent: 60/40 cyclohexane/EtOAc).The pure fractions were collected and the solvent was evaporated,yielding 0.8 g of intermediate 34.

e) Preparation of Intermediate 35

Methylmagnesium chloride (12.9 mmol) was added dropwise to a solution ofintermediate 34 (4 mmol) in THE (15 ml) at 5° C. under N₂. The reactionmixture was stirred at room temperature for 30 minutes. NH₄Cl 10%aqueous solution was added carefully at 5° C. EtOAc was added and thereaction mixture was extracted. The organic layer was separated, driedover MgSO₄, filtered and evaporated. The residue (1.3 g) was purified bycolumn chromatography (eluent: 70/30 cyclohexane/EtOAc). The purefractions were collected and the solvent was evaporated, yielding 0.8 gof intermediate 35.

f) Preparation of Intermediate 36

A mixture of intermediate 35 (2.8 mmol), Raney Nickel (0.6 g) inCH₃OH/NH₃ (10 ml) was hydrogenated under a 3 bar pressure at roomtemperature for 2 hours. The residue was filtered over celite, washedwith CH₂Cl₂ and the solvent was evaporated, yielding 0.7 g ofintermediate 36.

g) Preparation of Intermediate 37

A mixture of intermediate 36 (1.60 mmol), 2,3-difluoro-6-nitroanisole(1.76 mmol), carbonic acid sodium salt (1.92 mmol) in DMSO (5 ml) washeated at 60° C. overnight. The mixture was cooled to room temperature.Ice water was added, CH₂Cl₂ was added. The reaction mixture wasextracted, the organic layer was separated, dried over MgSO₄, filteredand concentrated.

The residue (0.8 g) was purified by high-performance liquidchromatography (Irregular SiOH 15-40 μm 300 g MERCK/Mobilephase:cyclohexane 70% EtOAc 30%). The pure fractions were collected andthe solvent was evaporated, yielding 450 mg of intermediate 37.

h) Preparation of Intermediate 8

Intermediate 37 (1.03 mmol), Pt/C 5% (0.1 g), V₂O₅ (5 mg), thiophenesolution 4% in DIPE (30 μL) in THF (20 ml) were hydrogenated atatmospheric pressure for 1 night at room temperature. The reactionmixture was filtered over celite, washed with CH₂Cl₂ and the filtratewas evaporated, yielding 0.33 g of intermediate 38.

B. Preparation of the Final Compounds Example B1 Preparation of Compound11

A mixture of intermediate 2 (0.0012 mol), 4-bromopyridine, hydrochloride(1:1) (0.0012 mol) and DIPEA (0.001 mol) in CH₃CN (10 ml) was stirred at65° C. for 18 hours, then cooled to room temperature, poured out intoK₂CO₃ 10% aqueous solution and extracted with CH₂Cl₂/CH₃OH (few). Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness. The residue (0.47 g) was purified by columnchromatography over kromasil (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.3 to91/9/0.9; 3.5 μm). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from CH₃CN. The precipitate wasfiltered off and dried, yielding 0.163 g (36%) of compound 11 (M.P.:164° C.).

Compounds No. 12, 13 and 65 were made according to example B1.

Example B2 a) Preparation of Compound 3

A mixture of intermediate 4 (0.0002 mol), 4-bromopyridine, hydrochloride(1:1) (0.0002 mol) and DIPEA (0.0002 mol) in CH₃CN (1 ml) and EtOH (0.5ml) was stirred at 65° C. for 18 hours. HCl (0.2 eq) and dioxane 4N (14μl) were added. The mixture was stirred at 65° C. for 18 hours, thencooled to room temperature, diluted in CH₂Cl₂ and washed with K₂CO₃ 10%aqueous solution. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated till dryness. The residue (0.24g) was purified by column chromatography over Sunfire (eluent:CH₂Cl₂/CH₃OH/NH₄OH 100/0/0 to 93/7/0.7; 5 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.073 g, 57%) wascrystallized from CH₃CN. The precipitate was filtered off and dried,yielding 0.039 g (30%) of compound 3 (M.P.: 187° C.).

Compound No. 4 was made according to example B2a).

b) Preparation of Compound 5

A mixture of intermediate 4 (0.0002 mol) and4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.0002 mol) inHCl/dioxane 4N (14 μl), CH₃CN (1 ml) and EtOH (0.5 ml) was stirred at65° C. for 18 hours. HCl (0.2 eq) and dioxane 4N (14 μl) were added. Themixture was stirred at 65° C. for 18 hours, then cooled to roomtemperature, diluted in CH₂Cl₂ and washed with K₂CO₃ 10% aqueoussolution. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated till dryness. The residue (0.14 g) waspurified by column chromatography over Sunfire (eluent:CH₂Cl₂/CH₃OH/NH₄OH 100/0/0 to 92/8/0.8; 5 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.072 g, 50%) wascrystallized from CH₃CN. The precipitate was filtered off and dried,yielding 0.049 g (30%) of compound 5 (M.P.: 178° C.).

Example B3 Preparation of Compound 14

A mixture of intermediate 2 (0.0012 mol), 4-chloro-2-pyridinemethanol(0.0012 mol) and HCl/dioxane 4N (0.0002 mol) in CH₃CN (10 ml) wasstirred at 65° C. for 18 hours, then cooled to room temperature, pouredout into K₂CO₃ 10% aqueous solution and extracted with CH₂Cl₂/CH₃OH(few). The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated till dryness. The residue (0.52 g) was purifiedby column chromatography over kromasil (eluent: CH₂Cl₂/CH₃OH/NH₄OH97/3/0.3 to 91/9/0.9; 3-5 μm). The pure fractions were collected and thesolvent was evaporated. The residue (0.3 g, 60%) was crystallized fromCH₃CN. The precipitate was filtered off and dried, yielding 0.292 g(51%) of compound 14 as a hydrochloric acid salt (0.1.52HCl, M.P.: 110°C.).

Compounds No. 15, 16 and 60 were made according to example B3. pleaseconfirm

Example B4 a) Preparation of Compound 24

A mixture of intermediate 6a (0.0007 mol) and4-chloro-2-pyridinemethanol (0.0007 mol) in HCl/dioxane 4N (0.0001 mol),CH₃CN (2.5 ml) and EtOH (1 ml) was stirred at 65° C. for 18 hours. Themixture was cooled at room temperature, diluted with CH₂Cl₂ and washedwith K₂CO₃ 10% aqueous solution. The organic layer was decanted, dried(MgSO₄), filtered and the solvent was evaporated till 15 ml. The residuewas filtered off and dried, yielding 0.168 g (64%) of compound 24 (M.P.:115° C.).

b) Preparation of Compound 25

A mixture of intermediate 6b (0.0007 mol) and4-chloro-2-pyridinemethanol (0.0007 mol) in HCl/dioxane 4N (0.0001 mol),CH₃CN (2 ml) and EtOH (0.8 ml) was stirred at 65° C. for 18 hours. Themixture was cooled at room temperature, poured into K₂CO₃ 10% aqueoussolution and extracted with CH₂Cl₂. The precipitate was filtered, washedwith CH₃CN and dried, yielding 0.155 g (53%) of compound 25 (M.P.: 186°C.).

Compounds No. 26, 27 and 28 were made according to example B4b).

c) Preparation of Compound 31

A mixture of intermediate 6c (0.0008 mol) and 4-chloroquinoline (0.0009mol) in HCl/dioxane 4N (0.0001 mol), CH₃CN (2.5 ml) and EtOH (1 ml) wasstirred at 65° C. for 48 hours. The mixture was cooled at roomtemperature, poured into K₂CO₃ 10% aqueous solution and extracted withCH₂Cl₂. The precipitate was filtered, washed with CH₃CN and dried,yielding 0.266 g (71%) of compound 31 (M.P.: 175° C.).

Compounds No. 29, 30 and 32 were made according to example B4c).

Example B5 Preparation of Compound 17

A mixture of intermediate 2 (0.0012 mol),4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.0012 mol) andHCl/dioxane 4N (0.0025 mol) in CH₃CN (10 ml) was stirred at 65° C. for18 hours, then cooled to room temperature, poured out into K₂CO₃ 10%aqueous solution and extracted with CH₂Cl₂/CH₃OH (few). The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness. The residue (0.54 g) was purified by columnchromatography over kromasil (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.3 to88/12/1.2; 3-5 μm). The pure fractions were collected and the solventwas evaporated. The residue (0.14 g, 26%) was crystallized from CH₃CN.The precipitate was filtered off and dried, yielding 0.113 g (21%) ofcompound 17 (M.P.: 147° C.).

Compounds No. 18, 19, 20, 21, 22, 23, 33, 34, 35, 36, 37 and 61 weremade according to example B5.

Example B6 a) Preparation of Compound 9

A mixture of intermediate 8a (0.0006 mol) and4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.006 mol) inHCl/dioxane 4N (0.0001 mol), CH₃CN (2 ml) and CH₃OH (0.8 ml) was stirredat 65° C. for 18 hours then cooled at room temperature. 3N HCl (0.0025mol) was added. The mixture was stirred at 65° C. for 18 hours, cooledat room temperature, diluted with CH₂Cl₂ and washed with K₂CO₃ 10%aqueous solution. The organic layer was decanted, dried (MgSO₄),filtered and the solvent was evaporated till dryness. The residue (0.36g) was purified by column chromatography over kromasil (eluent:CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.2 to 90/10/1; 3.5 μm). The pure fractions(0.14 g) were crystallized from CH₃CN. The precipitate was filtered offand dried, yielding 0.120 g (47%) of compound 9 (M.P.: 207° C.).

Compounds No. 7 and 8 were made according to example B6a).

b) Preparation of Compound 10

A mixture of intermediate 8b (0.0007 mol) and4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.0008 mol) inHCl/dioxane 4N (0.0001 mol), CH₃CN (2 ml) and CH₃OH (0.8 ml) was stirredat 65° C. for 48 hours then cooled to room temperature, poured out tointo K₂CO₃ 10% aqueous solution and extracted with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by column chromatography overkromasil (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.2 to 90/10/1; 3.5 μm). Thepure fractions were collected and the solvent was evaporated tilldryness. The residue was crystallized from CH₃CN. The precipitate wasfiltered off and dried, yielding 0.055 g (17%) of compound 10 (M.P.:237° C.).

Example B7 Preparation of Compound 53

A mixture of intermediate 11 (0.0011 mol), 4-chloroquinoline (0.0012mol) and HCl/dioxane 4N (0.0002 mol) in CH₃CN (2.5 ml) and EtOH (1 ml)was stirred at 65° C. for 18 hours, then cooled to room temperature,poured out into K₂CO₃ 10% aqueous solution and extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. The precipitate was filtered off and dried, yielding0.366 g (66%) of compound 53 (M.P.: 192° C.).

Compounds No. 51, 52, 53 and 54 were made according to example B7.

Example B8 Preparation of Compound 59

A solution of intermediate 14 (0.0005 mol) in 3N HCl (5 ml) and THF (1ml) was stirred at 100° C. for 10 days. K₂CO₃ 10% aqueous solution andCH₂Cl₂ were added. The mixture was extracted. The organic layer wasseparated, dried (MgSO₄), filtered off and concentrated. The residue(0.2 g) was purified by column chromatography (eluent:CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.1). The residue (0.010 g, 5%) was purified bycolumn chromatography (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.7). The purefractions were collected and the solvent was evaporated, yielding 0.003g (1.5%) of compound 59.

Example B9 a) Preparation of Compound 1

A mixture of intermediate 16 (0.0005 mol), 4-bromopyridine,hydrochloride (1:1) (0.0005 mol) and DIPEA (0.0004 mol) in CH₃CN (1.5ml) and EtOH (0.5 ml) was stirred at 65° C. for 18 hours. HCl (0.2 eq)and dioxane 4N (29 μl) were added. The mixture was stirred at 65° C. for18 hours, then cooled to room temperature, poured out into K₂CO₃ 10%aqueous solution and extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated tilldryness. The residue (0.24 g) was purified by column chromatography overkromasil (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 10 μm). The purefractions were collected and the solvent was evaporated, yielding 0.039g (19%) of compound 1 (M.P.: 186° C.).

b) Preparation of Compound 2

A mixture of intermediate 16 (0.0005 mol), 4-chloro-2-pyridinemethanol(0.0005 mol) and HCl/dioxane 4N (0.0001 mol) in CH₃CN (1.5 ml) and EtOH(0.5 ml) was stirred at 65° C. for 18 hours. HCl (0.2 eq) and dioxane 4N(29 μl) were added. The mixture was stirred at 65° C. for 18 hours, thencooled to room temperature, poured out into K₂CO₃ 10% aqueous solutionand extracted with EtOAc. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated till dryness. Theresidue (0.18 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 10 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.03 g, 14%) wascrystallized from CH₃CN/DIPE. The precipitate was filtered off anddried, yielding 0.03 g (9%) of compound 2 (M.P.: 163° C.).

Example B10 Preparation of Compound 55

A mixture of intermediate 18 (0.0008 mol) and 4-bromopyridine,hydrochloride (1:1) (0.0008 mol) in DIPEA (0.0006 mol), CH₃CN (2.5 ml)and EtOH (1 ml) was stirred at 65° C. for 18 hours then cooled at roomtemperature, poured out into K₂CO₃ 10% aqueous solution and extractedwith CH₂Cl₂. The organic layer was decanted, dried (MgSO₄), filtered andthe solvent was evaporated till dryness. The residue (0.357 g) waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5; 15-40 μm). The solvent of pure fractionswas evaporated till dryness. The residue (0.135 g) was crystallized fromCH₃CN/EtOH/DIPE, yielding 0.126 g (35%) of compound 55 as a hydrochloricacid salt (0.0.99HCl, M.P.: 245° C.).

Compounds No. 56, 57 and 58 were made according to example B10.

Example B11 Preparation of Compound 50

A mixture of intermediate 20 (0.001 mol), 4-bromopyridine, hydrochloride(1:1) (0.001 mol) and DIPEA (0.0008 mol) in CH₃CN (2.5 ml) and EtOH (1ml) was stirred at 65° C. for 18 hours, then cooled to room temperature,poured out into K₂CO₃ 10% aqueous solution and extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated till dryness. The residue (0.37 g) was purified by columnchromatography over kromasil (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.2 to88/12/1.2; 3.5 μm). The pure fractions were collected and the solventwas evaporated till dryness. The residue was crystallized from CH₃CN.The precipitate was filtered off and dried, yielding 0.095 g (23%) ofcompound 50 (M.P.: 241° C.).

Example B12 Preparation of Compound 49

A mixture of intermediate 22 (0.0015 mol) and4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.0016 mol) inHCl/dioxane 4N (0.0003 mol), CH₃CN (3 ml) and EtOH (1.2 ml) was stirredat 65° C. for 18 hours then cooled at room temperature, poured out intoK₂CO₃ 10% aqueous solution and extracted with CH₂Cl₂. The organic layerwas decanted, dried (MgSO₄), filtered and the solvent was evaporatedtill dryness. The residue (0.74 g) was purified by column chromatographyover kromasil (eluent: CH₂Cl₂/CH₃OH/NH₄OH 100 to 93/7/0.7; 5 μm). Thesolvent was evaporated till dryness. The residue (0.445 g) wascrystallized from EtOH. The residue was filtered off and dried, yielding0.244 g (36%) of compound 49 (M.P.: 123° C.).

Compounds No. 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and 48 were madeaccording to example B12.

Example B13 Preparation of Compound 6

A mixture of intermediate 24 (0.0008 mol) and 4-bromo-pyridine,hydrochloride (1:1) (0.0008 mol) in DMF (3 ml) was stirred at 105° C.for 1 hour and 30 minutes, then cooled to room temperature and pouredout into K₂CO₃ 10% aqueous solution. The precipitate was filtered,washed with water several times and taken up in CH₂Cl₂/CH₃OH (few). Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness. The residue (0.38 g) was purified by columnchromatography over kromasil (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.4 to88/12/1.2; 5 μm). The pure fractions were collected and the solvent wasevaporated. The crude oil (0.09 g, 23%) was dissolved in isopropanol andcooled in a bath of ice. HCl/isopropanol 5N (2 eq) was added. Theprecipitate was filtered off and dried, yielding 0.063 g (16%) ofcompound 6 (melting point: 166° C.).

Example B14 Preparation of Compound 62

Lithium aluminium hybrid in 1M THF (0.398 mmol) was added portionwise toa solution of intermediate 30 in THF at 5° C. The mixture was stirredfor 2 hours at room temperature. Water was added carefully at 5° C.EtOAc was added. The reaction mixture was filtered over celite andextracted. The organic layer was separated, dried over MgSO₄, filteredand concentrated. The crude (0.12 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5; 30g 15-40 μm). The pure fractions were collected and the solvent wasevaporated, yielding 0.042 g of compound 62.

Example B15 Preparation of Compounds 63 and 64

A solution of intermediate 38 (0.92 mmol),4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (1 mmol), hydrogenchloride in dioxane 4M (46 μl) in CH₃CN (10 ml) was heated at 65° C. for5 hours. K₂CO₃ 10% aqueous solution and EtOAc were added. The reactionmixture was extracted, the organic layer was separated, dried overMgSO₄, filtered and evaporated. The residue (0.4 g) was purified byhigh-performance liquid chromatography (Stability Silica 5 μm 150×30.0mm). Mobile phase (NH₄OH 0.2%; gradient CH₂Cl₂/CH₃OH from 98/2 to88/12), yielding 49 mg compound 63 and 114 mg of compound 64.

C. Pharmacological Example

A2780 cells are human ovarian carcinoma cells with wild type p53.

The capacity of the compounds to preserve p53 in A2780 cells wasmeasured with the p53 enzyme linked immunosorbent assay (ELISA). The p53assay is a “sandwich” enzyme immunoassay employing two polyclonalantibodies. A polyclonal antibody, specific for the p53 protein, hasbeen immobilized onto the surface of the plastic wells. Any p53 presentin the sample to be assayed will bind to the capture antibody. Thebiotinylated detector polyclonal antibody also recognizes p53 protein,and will bind to any p53, which has been retained by the captureantibody. The detector antibody, in turn, is bound by horseradishperoxidase-conjugated streptavidin. The horseradish peroxidase catalysesthe conversion of the chromogenic substrate o-phenylene diamine, theintensity of which is proportional to the amount of p53 protein bound tothe plate. The coloured reaction product is quantified using aspectrophotometer. Quantitation is achieved by the construction of astandard curve using known concentrations of purified recombinant HIStagged p53 protein (see example C.1).

Cellular activity of the compounds of formula (I) was determined onA2780 tumour cells using a colorimetric assay for cell toxicity orsurvival (see example C.2).

C.1 P53 ELISA

A2780 cells (ATCC) were cultivated in RPMI 1640 supplemented with 10%fetal calf serum (FCS), 2 mM L-glutamine and gentamycin at 37° C. in ahumidified incubator with 5% CO₂.

A2780 cells were seeded at 20.000 cells per well in a 96 well plate,cultured for 24 hours and treated with compound for 16 hours at 37° C.in a humidified incubator. After incubation, the cells were washed oncewith phosphate-buffered saline and 30 μl, per well, low salt RIPA buffer(20 mM tris, pH7.0, 0.5 mM EDTA, 1% Nonidet P40, 0.5% DOC, 0.05% SDS, 1mM PMSF, 1 μg/ml aprotinin and 0.5 μ/ml leupeptin) was added. Plateswere placed on ice for 30 minutes to complete the lysis. p53 protein wasdetected in de lysates by using the sandwich ELISA, described below.

High binding polystyrene EIA/RIA 96 well plates (Costar 9018) werecoated with the capture antibody pAb1801 (Abcam ab28-100) at aconcentration of 1 μg/ml in coating buffer (0.1 M NaHCO₃ pH8.2), 50 μlper well. The antibody was allowed to adhere overnight at 4° C. Coatedplates were washed once with phosphate-buffered saline (PBS)/0.05% Tween20 and 300 μl of blocking buffer (PBS, 1% bovine serum albumins (BSA))was added, for an incubation period of 2 hours at room temperature.Dilutions of purified recombinant HIS tagged p53 protein, ranging from3-200 ng/ml, were made in blocking buffer and used as standards.

Plates were washed twice with PBS/0.05% Tween 20 and blocking buffer orstandards were added at 80 μl/well. To the standards, 20 μl of lysisbuffer was added. The samples were added to the other wells at 20 μllysate/well. After an overnight incubation at 4° C., plates were washedtwice with PBS/0.05% Tween 20. Aliquots of 100 μl secondary polyclonalantibody p53(FL-393) (Tebubio, sc-6243) at a concentration of 1 μg/ml inblocking buffer were added to each well and allowed to adhere for 2hours at room temperature. Plates were washed three times with PBS/0.05%Tween 20. Detection antibody anti-rabbit HRP (sc-2004, Tebubio) at 0.04μg/ml in PBS/1% BSA was added and incubated for 1 hour at roomtemperature. Plates were washed three times with PBS/0.05% Tween 20 and100 μl of substrate buffer was added (substrate buffer was preparedshortly before use by adding 1 tablet of 10 mg o-phenylene diamine (OPD)from Sigma and 125 μl 3% H₂O₂ to 25 ml OPD buffer: 35 mM citric acid, 66mM Na₂HPO₄, pH5.6). After 5 to 10 minutes, colour reaction was stoppedby adding 50 μl stop buffer (1 M H₂SO₄) per well. The absorbance at dualwavelengths of 490/655 nm was measured using a Biorad micro plate readerand the results were then analyzed.

For each experiment, controls (containing no drug) and a blankincubation (containing no cells or drugs) were run in parallel. Theblank value was subtracted from all control and sample values. For eachsample, the value of p53 (in absorbance units) was expressed as thepercentage of the value for p53 present in the control. Percentagepreservation higher than 140% was defined as significant. Herein theeffects of test compounds are expressed as the lowest dose giving atleast 140% of the value for p53 present in the control (LAD) (see Table3 below).

In some of the experiments the assay was adapted for and used in384-well culture plates

TABLE 3 Results of the compounds that were tested in the above p53 ELISAprotocol (A2780 cells) Comp. p53-elisa No. LAD [microM] 1 >10.0 2 3.03 >10.0 4 >10.0 5 0.3 6 1.0 7 >10.0 8 >10.0 9 >10.0 10 1.0 11 >10.0 1210.0 13 >10.0 14 >10.0 15 >10.0 16 >10.0 17 1.0 18 >10.0 19 >10.020 >10.0 21 >10.0 22 >10.0 23 >10.0 24 >10.0 25 3.0 26 >10.0 27 >10.028 >10.0 29 1.0 30 1.0 31 1.0 32 >10.0 33 3.0 34 1.0 35 1.0 36 10.0 373.0 38 3.0 39 0.1 40 1.0 41 0.3 42 0.1 43 0.3 44 1.0 45 1.0 46 1.0 470.1 48 1.0 49 1.0 50 >10.0 51 >10.0 52 >10.0 53 >10.0 54 >10.0 55 >10.056 >10.0 57 >10.0 58 >10.0 59 — 60 >10.0 61 0.3 62 3.0 63 1.0 64 0.3 65>10.0C.2 Proliferation Assay

The human U87MG glioma cells were cultured in DMEM medium supplementedwith 2 mM L-Glutamine, 1 mM Sodium Pyruvate, 1.5 g/L Sodium Bicarbonate,50 μg/ml gentamicin and 10% heat inactivated fetal calf serum. (U87MGcells are human glioblastoma cells with wild type p53. In this cell lineMDM2 tightly controls p53 expression).

The human A2780 ovarian cancer cells were a kind gift from Dr. T. C.Hamilton (Fox Chase Cancer Centre, Pennsylvania, U.S.A.). The cells werecultured in RPMI 1640 medium supplemented with 2 mM L-Glutamine, 50μg/ml gentamicin and 10% fetal calf serum.

Reagents Used in the Alamar Blue Assay

Resazurin was purchased from Aldrich (Prod. No. 199303). Potassiumferrocyanide, potassium ferricyanide, KH₂PO₄ and K₂HPO₄ were purchasedfrom Sigma (Prod. Nos. P9387, P8131, P5655 and P8281, respectively).

Potassium Phosphate Buffer 0.1 M (PPB) was made as follows: 2.72 gramKH₂PO₄ and 13.86 gram K₂HPO₄ were dissolved in 500 ml milli-Q H₂O, thepH was adjusted to pH 7.4 and the volume was brought to 1 litre withmilli-Q H₂O; the buffer was filter sterilised and stored at roomtemperature. Resazurin stock solution (PPB-A) was prepared fresh bydissolving 45 mg resazurin in 15 ml PBS. 30 mM potassium ferricyanide(PPB-B) was prepared by dissolving 0.987 gram potassium ferricyanide in100 ml PPB. 30 mM potassium ferrocyanide (PPB-C) was prepared bydissolving 1.266 gram potassium ferrocyanide in 100 ml PPB.

Mixture of PPB-A, PPB-B and PPB-C was prepared by mixing equal volumesof the respective solutions. Resazurin work solution (herein termed“Alamar Blue” solution) was prepared by diluting said mixture20×(vol/vol) in PPB and filter sterilising; the Alamar Blue solutioncould be kept at 4° C. for a maximum of 2 weeks.

Procedure of the Alamar Blue Assay

For experiments in 384 wells plates the cells were seeded at a densityof 5×10³ cells/ml in Falcon 384-well culture plates (Life Technologies,Merelbeke, Belgium), black with clear bottom, in 45 μl culture medium.Cells were allowed to adhere to plastic for 24 hr. The tested compoundwas pre-diluted (1/50 in culture medium) and 5 μl pre-diluted compoundwas added to the wells. Following 4-day incubation, 10 μl of the AlamarBlue solution was added to each well and the cells were furtherincubated for 5 hrs (A2780) or 6 hrs (U87MG) at 37° C. The fluorescenceintensity was measured for each well with a Fluorescence plate reader(Fluorskan, Labsystems, 540 nm excitation and 590 nm emission)

The antiproliferative activity was calculated as percentage of remainingviable cells in treated versus control (untreated cells) conditions.Within an experiment, the result for each experimental condition is themean of 3 replicate wells. When appropriate, the experiments wererepeated to establish full concentration-response curves. Whenappropriate, IC₅₀-values (concentration of the drug, needed to reducecell growth to 50% of the control) were computed using probit analysisfor graded data (Finney, D. J., Probit Analyses, 2^(nd) Ed. Chapter 10,Graded Responses, Cambridge University Press, Cambridge 1962). Hereinthe effects of test compounds are expressed as pIC₅₀ (the negative logvalue of the IC₅₀-value) (see Table 4).

TABLE 4 Results of the compounds that were tested in the above cellproliferation protocol A2780 cell U87MG cell proliferation proliferationComp. inhibition inhibition No. pIC₅₀ pIC₅₀ 1 <5 <5 2 <5 5.11 3 <5 <5 4<5 <5 5 <5 <5 6 <5 5.80 7 5.08 <5 8 <5 5.41 9 5.38 <5 10 5.45 5.55 11 <55.31 12 <5 5.62 13 <5 5.18 14 <5 <5 15 <5 ~5.23 16 <5 <5 17 5.08 5.16 18<5 5.17 19 <5 5.15 20 <5 <5 21 <5 <5 22 <5 5.29 23 <5 <5 24 <5 <5 25 <5<5 26 <5 <5 27 <5 <5 28 <5 <5 29 5.58 <5 30 5.08 5.06 31 ~5.59 5.88 32<5 5.48 33 <5 <5 34 5.67 5.14 35 <5 <5 36 <5 5.08 37 <5 <5 38 ~5.23 6.0639 ~5.59 6.07 40 ~5.19 5.86 41 5.38 5.83 42 6.15 6.75 43 5.56 5.81 44~5.96 6.56 45 6.39 6.14 46 ~5.46 6.08 47 ~5.74 6.35 48 <5 5.26 49 6.306.19 50 <5 <5 51 <5 5.20 52 <5 5.33 53 <5 5.40 54 <5 — 55 <5 <5 56 <5 —57 <5 <5 58 <5 <5 59 — — 60 <5 5.18 61 <5 5.23 62 6.04 5.89 63 7.13 6.3364 7.07 6.47 65 <5 5.26 ~means approximate

D. Analytical Data

Liquid Chromatography (LC) General Procedure

The LC measurement was performed using a UPLC (Ultra Performance LiquidChromatography) Acquity (Waters) system comprising a binary pump withdegasser, an autosampler, a diode-array detector (DAD) and a column asspecified in the respective methods below, the column is hold at atemperature of 40° C. Flow from the column was brought to a MS detector.The MS detector was configured with an electrospray ionization source.The capillary needle voltage was 3 kV and the source temperature wasmaintained at 130° C. on the Quattro (triple quadrupole massspectrometer from Waters). Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

In addition to the above general procedure: Reversed phase UPLC wascarried out on a Waters Acquity BEH (bridged ethylsiloxane/silicahybrid) C18 column (1.7 μm, 2.1×100 mm) with a flow rate of 0.35 ml/min.Two mobile phases (mobile phase A: 95% 7 mM ammonium acetate/5%acetonitrile; mobile phase B: 100% acetonitrile) were employed to run agradient condition from 90% A and 10% B (hold for 0.5 minutes) to 8% Aand 92% B in 3.5 minutes, hold for 2 min and back to the initialconditions in 0.5 min, hold for 1.5 minutes. An injection volume of 2was used. Cone voltage was 20 V for positive and negative ionizationmode. Mass spectra were acquired by scanning from 100 to 1000 in 0.2seconds using an interscan delay of 0.1 seconds.

TABLE 5 Analytical LCMS data: R_(t) is retention time in minutes; [MH]⁺means the protonated mass of the compound; Compound No. R_(t) [MH]⁺ 599.28 411 62 2.91 463 63 3.23 491 64 3.72 473

E. Composition Example: Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulphate and 10 g polyvinyl-pyrrolidone in about 200 mlof water. The wet powder mixture is sieved, dried and sieved again. Thenthere is added 100 g microcrystalline cellulose and 15 g hydrogenatedvegetable oil. The whole is mixed well and compressed into tablets,giving 10.000 tablets, each comprising 10 mg of a compound of formula(I).

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

Preferably, where one of R² or R²⁰ together with R⁹ form a direct bond,said direct bond may connect to a carbon of the central phenyl ringadjacent (i.e., o-position) to the carbon of the central phenyl ring towhich the —(CH₂)_(m)— group is bound.

As can be appreciated, in compounds of formula (I), and in particular incompounds of any one of the above groups “G1” to “G17”, the substituentsR² and R²⁰ may be in ortho (o-), meta (m-) or para (p-) positionsrelative to one another on the central phenyl ring.

When R² and R²⁰ together form a bivalent radical of the formula—(CH₂)_(b)— wherein b is 3, 4 or 5, optionally substituted as above,then bonds of said bivalent radical are preferably attached in ortho(o-) positions relative to one another on the central phenyl ring.

As can be appreciated, in compounds of formula (I), and in particular incompounds of any one of the above groups “G1” to “G17”, the foursubstituents on the central phenyl ring may be in various positionsrelative to one another. For example and without limitation, incompounds where substituents on the central phenyl ring other than R²and R²⁰ are in the para position, i.e., 1-, 4-, the R² and R²⁰substituents may be in positions 2- and 3-, or in positions 2- and 5-,or in positions 2- and 6-, etc.

Table 2 lists preferred albeit non-limiting examples of compounds offormula (I) that were prepared in the present invention. The followingabbreviations were used in the table: .HCl stands for hydrochloric acidsalt, mp. stands for melting point.

The invention claimed is:
 1. A method of treating a disorder mediated bya p53-MDM2 interaction comprising administering to a patient in needthereof a compound of Formula (I):

including any stereochemically isomeric form thereof, wherein m is 0, 1or 2 and when m is 0 then a direct bond is intended; n is 0, 1, 2 or 3and when n is 0 then a direct bond is intended; p is 0 or 1 and when pis 0 then a direct bond is intended; s is 0 or 1 and when s is 0 then adirect bond is intended; t is 0 or 1 and when t is 0 then a direct bondis intended; X is C(═O) or CHR⁸, wherein R⁸ is hydrogen; C₁₋₆alkyl;C₃₋₇cycloalkyl; —C(═O)—NR¹⁷R¹⁸; carboxyl; arylC₁₋₆alkyloxycarbonyl;heteroaryl; heteroarylcarbonyl; heteroarylC₁₋₆alkyloxycarbonyl;piperazinylcarbonyl; pyrrolidinyl; piperidinylcarbonyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with a substituent that ishydroxy, amino, aryl, or heteroaryl; C₃₋₇cycloalkyl substituted with asubstituent that is hydroxy, amino, aryl or heteroaryl;piperazinylcarbonyl substituted with a substituent that is hydroxy,hydroxyC₁₋₆alkyl or hydroxyC₁₋₆alkyloxyC₁₋₆alkyl; pyrrolidinylsubstituted with hydroxyC₁₋₆alkyl; or piperidinylcarbonyl substitutedwith one or two substituents that are hydroxy, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyl(dihydroxy)C₁₋₆alkylor C₁₋₆alkyloxy(hydroxy)C₁₋₆alkyl; R¹⁷ and R¹⁸ are each independentlyhydrogen, C₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, arylC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl(C₁₋₆alkyl), orhydroxyC₁₋₆alkyl(arylC₁₋₆alkyl);

 is —CR⁹═C< and then the dotted line is a bond, —C(═O)—CH<, —C(═O)—N<,—CHR⁹—CH<, or —CHR⁹—N<, wherein each R⁹ is independently hydrogen orC₁₋₆alkyl, or wherein R⁹ together with one of R² or R²⁰ form a directbond; R¹ is hydrogen; aryl; heteroaryl; C₁₋₆alkyloxycarbonyl;C₁₋₁₂alkyl; or C₁₋₁₂alkyl substituted with one or two substituents thatare hydroxy, aryl, heteroaryl, amino, C₁₋₆alkyloxy, mono- ordi(C₁₋₆alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,C₁₋₆alkylpiperazinyl, arylC₁₋₆alkylpiperazinyl,heteroarylC₁₋₆alkylpiperazinyl, C₃₋₇cycloalkyl-piperazinyl, orC₃₋₇cycloalkylC₁₋₆alkylpiperazinyl; R² and R²⁰ are each independentlyhalo, hydroxy, cyano, nitro, carboxyl; polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, aryl,heteroaryl, arylC₁₋₆alkyl, heteroaryl-C₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆alkyl, morpholinyl, piperidinyl, pyrrolidinyl,piperazinyl, C₁₋₆alkyloxy, aryloxy, heteroaryloxy, C₁₋₆alkylthio,arylthio, heteroarylthio, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, C₁₋₆alkyloxycarbonyl,C₃₋₇cycloalkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,C₁₋₆alkylcarbonyloxy, C₃₋₇cycloalkylcarbonyloxy, arylcarbonyloxy orheteroarylcarbonyloxy, any of said groups being optionally andindependently substituted with one or more substituents that are halo,hydroxy, cyano, nitro, carboxyl, amino, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyl, polyhaloC₁₋₆alkyl, aryl, heteroaryl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl and C₁₋₆alkylcarbonyloxy; or—(CH₂)_(w)—(C(═O))_(y)NR²¹R²² wherein w is 0, 1, 2, 3, 4, 5 or 6 andwhen w is 0 then a direct bond is intended; y is 0 or 1 and when y is 0then a direct bond is intended; R²¹ and R²² are each independentlyhydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkylcarbonyl orarylC₁₋₆alkylcarbonyl, any of said groups being optionally andindependently substituted with one or more substituents that are halo,hydroxy, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl or heteroaryl; or R²¹ and R²²together with the nitrogen to which they are attached form morpholinyl,piperidinyl, pyrrolidinyl or piperazinyl, any of said groups beingoptionally and independently substituted with one or more substituentsthat are C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₆alkyl, arylC₁₋₆alkyl, or heteroarylC₁₋₆alkyl; or R²and R²⁰ together with the phenyl ring to which they are attached form anaphthalenyl group, optionally substituted with one or more substituentseach independently halo, hydroxy, amino, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl, or heteroaryl; or R²and R²⁰ together form a bivalent radical of the formula —(CH₂)_(b)—wherein b is 3, 4 or 5, optionally substituted with one or moresubstituents that are halo, hydroxy, amino, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl, or heteroaryl; or oneof R² or R²⁰ is as defined above and the other one of R² or R²⁰ togetherwith R⁹ form a direct bond; R³ is hydrogen; C₁₋₆alkyl; heteroaryl;C₃₋₇cycloalkyl; C₁₋₆alkyl substituted with a substituent that ishydroxy, amino, aryl, or heteroaryl; or C₃₋₇cycloalkyl substituted witha substituent that is hydroxy, amino, aryl, or heteroaryl; R⁴ and R⁵ areeach independently hydrogen, halo, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,polyhalo-C₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl, hydroxy, amino, C₂₋₆alkenylor C₁₋₆alkyloxy; or R⁴ and R⁵ together form a bivalent radical that ismethylenedioxy or ethylenedioxy; R⁶ is hydrogen, C₁₋₆alkyloxycarbonyl,or C₁₋₆alkyl; when p is 1 then R⁷ is hydrogen, arylC₁₋₆alkyl, hydroxy,or heteroarylC₁₋₆alkyl; Z is a radical that is:

wherein R¹⁰ or R¹¹ are each independently hydrogen, halo, hydroxy,amino, C₁₋₆alkyl, nitro, polyhaloC₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl,tetrazoloC₁₋₆alkyl, aryl, heteroaryl, arylC₁₋₆alkyl,heteroarylC₁₋₆alkyl, aryl(hydroxy)C₁₋₆alkyl,heteroaryl(hydroxy)C₁₋₆alkyl, arylcarbonyl, heteroarylcarbonyl,C₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, heteroarylC₁₋₆alkylcarbonyl,C₁₋₆alkyloxy, C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkyl(hydroxy)C₁₋₆alkyl,arylC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylcarbonyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, hydroxyC₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₂₋₆alkenyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, aminocarbonyl,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, hydroxycarbonyl,hydroxycarbonylC₁₋₆alkyl, or —(CH₂)_(v)—(C(═O))_(r)—(CHR¹⁹)_(u)—NR¹³R¹⁴,wherein v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0 then a direct bondis intended; r is 0 or 1 and when r is 0 then a direct bond is intended;u is 0, 1, 2, 3, 4, 5, or 6 and when u is 0 then a direct bond isintended; R¹⁹ is hydrogen or C₁₋₆alkyl; R¹³ and R¹⁴ are eachindependently hydrogen; C₁₋₁₂alkyl; C₁₋₆alkylcarbonyl;C₁₋₆alkylsulfonyl; arylC₁₋₆alkylcarbonyl; C₃₋₇cycloalkyl;C₃₋₇cycloalkylcarbonyl; —(CH₂)_(k)—NR¹⁵R¹⁶; C₁₋₁₂alkyl substituted witha substituent that is hydroxy, hydroxycarbonyl, cyano,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, aryl or heteroaryl; orC₃₋₇cycloalkyl substituted with a substituent that is hydroxy,C₁₋₆alkyloxy, aryl, amino, arylC₁₋₆alkyl, heteroaryl orheteroarylC₁₋₆alkyl; or R¹³ and R¹⁴ together with the nitrogen to whichthey are attached form morpholinyl, piperidinyl, pyrrolidinyl,piperazinyl, or piperazinyl substituted with a substituent that isC₁₋₆alkyl, arylC₁₋₆alkyl, arylC₁₋₆alkyloxycarbonyl, heteroarylC₁₋₆alkyl,C₃₋₇cycloalkyl, or C₃₋₇cycloalkylC₁₋₆alkyl; wherein k is 0, 1, 2, 3, 4,5, or 6 and when k is 0 then a direct bond is intended; R¹⁵ and R¹⁶ areeach independently hydrogen; C₁₋₁₂alkyl; arylC₁₋₆alkyloxycarbonyl;C₃₋₇cycloalkyl; C₁₋₁₂alkyl substituted with a substituent that ishydroxy, C₁₋₆alkyloxy, aryl, or heteroaryl; or C₃₋₇cycloalkylsubstituted with a substituent that is hydroxy, C₁₋₆alkyloxy, aryl,arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; or R¹⁵ and R¹⁶together with the nitrogen to which they are attached form morpholinyl,piperazinyl, or piperazinyl substituted with C₁₋₆alkyloxycarbonyl; R¹²is hydrogen; C₁₋₆alkyl; C₃₋₇cycloalkyl; C₁₋₆alkyl substituted with asubstituent that is hydroxy, amino, C₁₋₆alkyloxy, or aryl; orC₃₋₇cycloalkyl substituted with a substituent that is hydroxy, amino,aryl, or C₁₋₆alkyloxy; aryl is phenyl or naphthalenyl; each phenyl ornaphthalenyl can optionally be substituted with one, two or threesubstituents each independently halo, hydroxy, C₁₋₆alkyl, amino,polyhaloC₁₋₆alkyl or C₁₋₆alkyloxy; and each phenyl or naphthalenyl canoptionally be substituted with a bivalent radical that is methylenedioxyor ethylenedioxy; heteroaryl is pyridinyl, indolyl, quinolinyl,imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl ortetrahydrofuranyl; each pyridinyl, indolyl, quinolinyl, imidazolyl,furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, ortetrahydrofuranyl can optionally be substituted with one, two or threesubstituents each independently halo, hydroxy, C₁₋₆alkyl, amino,polyhaloC₁₋₆alkyl, aryl, arylC₁₋₆alkyl or C₁₋₆alkyloxy; or eachpyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl,benzofuranyl, or tetrahydrofuranyl can optionally be substituted with abivalent radical that is methylenedioxy or ethylenedioxy; wherein whenR² or R²⁰ is C₁₋₆alkyl or C₁₋₆alkyloxy, then R² or R²⁰ is not fluorine;an N-oxide form thereof, an addition salt thereof or a solvate thereof.2. The method according to claim 1, wherein R⁴ and R⁵ are eachindependently hydrogen, halo, C₁₋₆alkyl, polyhaloC₁₋₆alkyl, cyano,cyanoC₁₋₆alkyl, hydroxy, amino, or C₁₋₆alkyloxy, or R⁴ and R⁵ togetherform a bivalent radical that is methylenedioxy or ethylenedioxy; R¹⁵ andR¹⁶ are each independently hydrogen, C₁₋₆alkyl,arylC₁₋₆alkyloxycarbonyl, C₃₋₇cycloalkyl, C₁₋₁₂alkyl substituted with asubstituent that is from hydroxy, C₁₋₆alkyloxy, aryl, or heteroaryl, orC₃₋₇cycloalkyl substituted with a substituent selected from hydroxy,C₁₋₆alkyloxy, aryl, arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl,or R¹⁵ and R¹⁶ together with the nitrogen to which they are attachedform morpholinyl, piperazinyl, or piperazinyl substituted withC₁₋₆alkyloxycarbonyl.
 3. The method according to claim 1, wherein

is —CR⁹═C< and then the dotted line is a bond, —C(═O)—CH<, —CHR⁹—CH<, or—CHR⁹—N<, wherein each R⁹ is independently hydrogen or C₁₋₆alkyl, orwherein R⁹ together with one of R² or R²⁰ form a direct bond.
 4. Themethod according to claim 3 wherein

is —CR⁹═C< and then the dotted line is a bond, —CHR⁹—CH<, or —CHR⁹—N<.5. The method according to claim 4 wherein

is —CR⁹═C< and then the dotted line is a bond.
 6. The method accordingto claim 1, wherein X is C(═O) or CHR⁸ and R⁸ is hydrogen;—C(═O)—NR¹⁷R¹⁸; arylC₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted withhydroxyl; piperazinylcarbonyl substituted with hydroxyl;hydroxyC₁₋₆alkyl; hydroxyC₁₋₆alkyloxyC₁₋₆alkyl; pyrrolidinyl substitutedwith hydroxyl-C₁₋₆alkyl; or piperidinylcarbonyl substituted with one ortwo substituents that are hydroxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyl(dihydroxy)C₁₋₆alkyl orC₁₋₆alkyloxy(hydroxy)C₁₋₆alkyl; R¹⁷ and R⁸ are each independentlyhydrogen, C₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, arylC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl or hydroxyC₁₋₆alkyl;

 is —CR⁹═C<, —CHR⁹—CH< or —CHR⁹—N<; R¹ is hydrogen, heteroaryl,C₁₋₆alkyloxycarbonyl, C₁₋₁₂alkyl or C₁₋₁₂alkyl substituted withheteroaryl; R³ is hydrogen, C₁₋₆alkyl or heteroaryl; R⁴ and R⁵ are eachindependently hydrogen, halo, C₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl, hydroxyor C₁₋₆alkyloxy; when p is 1 then R⁷ is arylC₁₋₆alkyl or hydroxy; Z is a(a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8) or (a-9); R¹⁰ orR¹¹ are each independently hydrogen, halo, hydroxy, amino, C₁₋₆alkyl,nitro, polyhaloC₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl, tetrazoloC₁₋₆alkyl,aryl, heteroaryl, heteroarylC₁₋₆alkyl, aryl(hydroxy)C₁₋₆alkyl,arylcarbonyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkylcarbonyl,C₃₋₇cycloalkyl(hydroxy)C₁₋₆alkyl, arylC₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylcarbonyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, hydroxyC₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₂₋₆alkenyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, aminocarbonyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,hydroxycarbonyl, hydroxycarbonylC₁₋₆alkyl or—(CH₂)_(v)—(C(═O))_(r)—(CHR¹⁹)_(u)—NR¹³R¹⁴; v is 0 or 1; u is 0 or 1;R¹² is hydrogen or C₁₋₆alkyl; R¹³ and R¹⁴ are each independentlyhydrogen; C₁₋₁₂alkyl; C₁₋₆alkylcarbonyl; C₁₋₆alkylsulfonyl;arylC₁₋₆alkylcarbonyl; C₃₋₇cycloalkylcarbonyl; —(CH₂)_(k)—NR¹⁵R¹⁶;C₁₋₁₂alkyl substituted with a substituent that is hydroxy,hydroxycarbonyl, cyano, C₁₋₆alkyloxycarbonyl or aryl; or R¹³ and R¹⁴together with the nitrogen to which they are attached form morpholinyl,pyrrolidinyl, piperazinyl or piperazinyl substituted with a substituentthat is C₁₋₆alkyl or arylC₁₋₆alkyloxycarbonyl; k is 2; R¹⁵ and R¹⁶ areeach independently hydrogen, C₁₋₆alkyl or arylC₁₋₆alkyloxycarbonyl; orR¹⁵ and R¹⁶ together with the nitrogen to which they are attached formmorpholinyl or piperazinyl, or piperazinyl substituted withC₁₋₆alkyloxycarbonyl; aryl is phenyl or phenyl substituted with halo;and heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl; andeach pyridinyl, indolyl, oxadiazolyl or tetrazolyl can optionally besubstituted with one substituent that is C₁₋₆alkyl, aryl orarylC₁₋₆alkyl.
 7. The method of claim 1, wherein s is 0; t is 0; m is 0;p is 0; n is 1 or 2; R¹ is hydrogen; R³ is hydrogen; R⁴ and R⁵ are eachindependently hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyl,C₂₋₆alkenyl; R⁶ is hydrogen;

 is —CR⁹═C< and then the dotted line is a bond; R⁹ is hydrogen orC₁₋₆alkyl; X is CH₂; Z is a (a-1), (a-2) or (a-4); R¹⁰ and R¹¹ are eachindependently hydrogen, hydroxy or hydroxyC₁₋₆alkyl.
 8. The method ofclaim 1, wherein R² and R²⁰ are each independently halo, cyano,polyhaloC₁₋₆alkyl, C₁₋₆alkyl, morpholinyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyl, or —NR²¹R²² wherein R²¹ is hydrogen and R²² isC₁₋₆alkylcarbonyl; or R² and R²⁰ together with the phenyl ring to whichthey are attached form a naphthalenyl group, or one of R² or R²⁰ is asdefined above and the other one of R² or R²⁰ together with R⁹ form adirect bond.
 9. A method of treating a disorder mediated by a p53-MDM2interaction comprising administering to a patient in need thereof acompound that is:

a stereochemically isomeric form thereof; an N-oxide form thereof, anaddition salt thereof or a solvate thereof.
 10. A method of treating acancer that is mediated through a p53-MDM2 interaction, comprisingadministering to a patient in need thereof a compound of Formula (I):

including any stereochemically isomeric form thereof, wherein m is 0, 1or 2 and when m is 0 then a direct bond is intended; n is 0, 1, 2 or 3and when n is 0 then a direct bond is intended; p is 0 or 1 and when pis 0 then a direct bond is intended; s is 0 or 1 and when s is 0 then adirect bond is intended; t is 0 or 1 and when t is 0 then a direct bondis intended; X is C(═O) or CHR⁸, wherein R⁸ is hydrogen; C₁₋₆alkyl;C₃₋₇cycloalkyl; —C(═O)—NR¹⁷R¹⁸; carboxyl; arylC₁₋₆alkyloxycarbonyl;heteroaryl; heteroarylcarbonyl; heteroarylC₁₋₆alkyloxycarbonyl;piperazinylcarbonyl; pyrrolidinyl; piperidinylcarbonyl;C₁₋₆alkyloxycarbonyl; C₁₋₆ alkyl substituted with a substituent that ishydroxy, amino, aryl, or heteroaryl; C₃₋₇cycloalkyl substituted with asubstituent that is hydroxy, amino, aryl, or heteroaryl;piperazinylcarbonyl substituted with a substituent that is hydroxy,hydroxyC₁₋₆alkyl, or hydroxyC₁₋₆alkyloxyC₁₋₆alkyl; pyrrolidinylsubstituted with hydroxyC₁₋₆alkyl; or piperidinylcarbonyl substitutedwith one or two substituents that are hydroxy, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyl(dihydroxy)C₁₋₆alkyl,or C₁₋₆alkyloxy(hydroxy)C₁₋₆alkyl; R¹⁷ and R¹⁸ are each independentlyhydrogen, C₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, arylC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl(C₁₋₆alkyl), orhydroxyC₁₋₆alkyl(arylC₁₋₆alkyl);

 is —CR⁹═C< and then the dotted line is a bond, —C(═O)—CH<, —C(═O)—N<,—CHR⁹—CH<, or —CHR⁹—N<, wherein each R⁹ is independently hydrogen orC₁₋₆alkyl, or wherein R⁹ together with one of R² or R²⁰ form a directbond; R¹ is hydrogen; aryl; heteroaryl; C₁₋₆alkyloxycarbonyl;C₁₋₁₂alkyl; or C₁₋₁₂alkyl substituted with one or two substituentsindependently that are hydroxy, aryl, heteroaryl, amino, C₁₋₆alkyloxy,mono- or di(C₁₋₆alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl,piperazinyl, C₁₋₆alkylpiperazinyl, arylC₁₋₆alkylpiperazinyl,heteroarylC₁₋₆alkylpiperazinyl, C₃₋₇cycloalkyl-piperazinyl, orC₃₋₇cycloalkylC₁₋₆alkylpiperazinyl; R² and R²⁰ are each independentlyhalo, hydroxy, cyano, nitro, carboxyl; polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, aryl,heteroaryl, arylC₁₋₆alkyl, heteroaryl-C₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆alkyl, morpholinyl, piperidinyl, pyrrolidinyl,piperazinyl, C₁₋₆alkyloxy, aryloxy, heteroaryloxy, C₁₋₆alkylthio,arylthio, heteroarylthio, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, C₁₋₆alkyloxycarbonyl,C₃₋₇cycloalkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,C₁₋₆alkylcarbonyloxy, C₃₋₇cycloalkylcarbonyloxy, arylcarbonyloxy orheteroarylcarbonyloxy, any of said groups being optionally andindependently substituted with one or more substituents that are halo,hydroxy, cyano, nitro, carboxyl, amino, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyl, polyhaloC₁₋₆alkyl, aryl, heteroaryl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl or C₁₋₆alkylcarbonyloxy; or—(CH₂)_(w)—(C(═O))_(y)NR²¹R²² wherein w is 0, 1, 2, 3, 4, 5 or 6 andwhen w is 0 then a direct bond is intended; y is 0 or 1 and when y is 0then a direct bond is intended; R²¹ and R²² are each independentlyhydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkylcarbonyl, orarylC₁₋₆alkylcarbonyl, any of said groups being optionally andindependently substituted with one or more substituents that are halo,hydroxy, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl, or heteroaryl; or R²¹ and R²²together with the nitrogen to which they are attached form morpholinyl,piperidinyl, pyrrolidinyl or piperazinyl, any of said groups beingoptionally and independently substituted with one or more one or two,substituents that are C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy,C₃₋₇cycloalkyl, C3-7cycloalkylC₁₋₆alkyl, arylC₁₋₆alkyl, orheteroarylC₁₋₆alkyl; or R² and R²⁰ together with the phenyl ring towhich they are attached form a naphthalenyl group, optionallysubstituted with one or more substituents each independently that arehalo, hydroxy, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl, or heteroaryl; or R² and R²⁰together form a bivalent radical of the formula —(CH₂)_(b)—, wherein bis 3, 4 or 5, optionally substituted with one or more substituents thatare halo, hydroxy, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl, or heteroaryl; or one of R² orR²⁰ is as defined above and the other one of R² or R²⁰ together with R⁹form a direct bond; R³ is hydrogen; C₁₋₆alkyl; heteroaryl;C₃₋₇cycloalkyl; C₁₋₆alkyl substituted with a substituent that ishydroxy, amino, aryl, or heteroaryl; or C₃₋₇cycloalkyl substituted witha substituent that is hydroxy, amino, aryl, or heteroaryl; R⁴ and R⁵ areeach independently hydrogen, halo, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,polyhalo-C₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl, hydroxy, amino, C₂₋₆alkenylor C₁₋₆alkyloxy; or R⁴ and R⁵ together form a bivalent radical that ismethylenedioxy or ethylenedioxy; R⁶ is hydrogen, C₁₋₆alkyloxycarbonyl,or C₁₋₆alkyl; when p is 1 then R⁷ is hydrogen, arylC₁₋₆alkyl, hydroxy,or heteroarylC₁₋₆alkyl; Z is a radical that is:

wherein R¹⁰ or R¹¹ are each independently hydrogen, halo, hydroxy,amino, C₁₋₆alkyl, nitro, polyhaloC₁₋₆alkyl, cyano, cyanoC₁₋₆alkyl,tetrazoloC₁₋₆alkyl, aryl, heteroaryl, arylC₁₋₆alkyl,heteroarylC₁₋₆alkyl, aryl(hydroxy)C₁₋₆alkyl,heteroaryl(hydroxy)C₁₋₆alkyl, arylcarbonyl, heteroarylcarbonyl,C₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, heteroarylC₁₋₆alkylcarbonyl,C₁₋₆alkyloxy, C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkyl(hydroxy)C₁₋₆alkyl,arylC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylcarbonyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, hydroxyC₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₂₋₆alkenyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, aminocarbonyl,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, hydroxycarbonyl,hydroxycarbonylC₁₋₆alkyl or —(CH₂)_(v)—(C(═O))_(r)—(CHR¹⁹)_(u)—NR¹³R¹⁴,wherein v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0 then a direct bondis intended; r is 0 or 1 and when r is 0 then a direct bond is intended;u is 0, 1, 2, 3, 4, 5, or 6 and when u is 0 then a direct bond isintended; R¹⁹ is hydrogen or C₁₋₆alkyl; R¹³ and R¹⁴ are eachindependently hydrogen; C₁₋₁₂alkyl; C₁₋₆alkylcarbonyl;C₁₋₆alkylsulfonyl; arylC₁₋₆alkylcarbonyl; C₃₋₇cycloalkyl;C₃₋₇cycloalkylcarbonyl; —(CH₂)_(k)—NR¹⁵R¹⁶; C₁₋₁₂alkyl substituted witha substituent that is hydroxy, hydroxycarbonyl, cyano,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, aryl or heteroaryl; orC₃₋₇cycloalkyl substituted with a substituent that is hydroxy,C₁₋₆alkyloxy, aryl, amino, arylC₁₋₆alkyl, heteroaryl orheteroarylC₁₋₆alkyl; or R¹³ and R¹⁴ together with the nitrogen to whichthey are attached form morpholinyl, piperidinyl, pyrrolidinyl,piperazinyl, or piperazinyl substituted with a substituent that isC₁₋₆alkyl, arylC₁₋₆alkyl, arylC₁₋₆alkyloxycarbonyl, heteroarylC₁₋₆alkyl,C₃₋₇cycloalkyl, or C₃₋₇cycloalkylC₁₋₆alkyl; wherein  k is 0, 1, 2, 3, 4,5, or 6 and when k is 0 then a direct bond is intended;  R¹⁵ and R¹⁶ areeach independently hydrogen; C₁₋₁₂alkyl; arylC₁₋₆alkyloxycarbonyl;C₃₋₇cycloalkyl; C₁₋₁₂alkyl substituted with a substituent that ishydroxy, C₁₋₆alkyloxy, aryl, or heteroaryl; or C₃₋₇cycloalkylsubstituted with a substituent that is hydroxy, C₁₋₆alkyloxy, aryl,arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; or  R¹⁵ and R¹⁶together with the nitrogen to which they are attached form morpholinyl,piperazinyl, or piperazinyl substituted with C₁₋₆alkyloxycarbonyl; R¹²is hydrogen; C₁₋₆alkyl; C₃₋₇cycloalkyl; C₁₋₆alkyl substituted with asubstituent that is hydroxy, amino, C₁₋₆alkyloxy, or aryl; orC₃₋₇cycloalkyl substituted with a substituent that is hydroxy, amino,aryl, or C₁₋₆alkyloxy; aryl is phenyl or naphthalenyl; each phenyl ornaphthalenyl can optionally be substituted with one, two or threesubstituents each independently halo, hydroxy, C₁₋₆alkyl, amino,polyhaloC₁₋₆alkyl or C₁₋₆alkyloxy; and each phenyl or naphthalenyl canoptionally be substituted with a bivalent radical that is methylenedioxyor ethylenedioxy; heteroaryl is pyridinyl, indolyl, quinolinyl,imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl ortetrahydrofuranyl; each pyridinyl, indolyl, quinolinyl, imidazolyl,furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, ortetrahydrofuranyl can optionally be substituted with one, two or threesubstituents each independently halo, hydroxy, C₁₋₆alkyl, amino,polyhaloC₁₋₆alkyl, aryl, arylC₁₋₆alkyl or C₁₋₆alkyloxy; or eachpyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl,benzofuranyl, or tetrahydrofuranyl can optionally be substituted with abivalent radical that is methylenedioxy or ethylenedioxy; wherein whenR² or R²⁰ is C₁₋₆alkyl or C₁₋₆alkyloxy, then R² or R²⁰ is not fluorine;an N-oxide form thereof, an addition salt thereof or a solvate thereof.11. The method of claim 1, where R² or R²⁰ are substituted with one ortwo substituents.
 12. The method of claim 1, where R²¹ or R²² aresubstituted with one or two substituents.
 13. The method of claim 1,wherein R²¹ and R²² together with the nitrogen to which they areattached form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl, anyof said groups are independently substituted with one or twosubstituents that are C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl, arylC₁₋₆alkyl, orheteroarylC₁₋₆alkyl.
 14. The method of claim 1, wherein R² and R²⁰together with the phenyl ring to which they are attached form anaphthalenyl group, substituted with one or two substituents eachindependently halo, hydroxy, amino, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl, or heteroaryl.
 15. Themethod of claim 1, wherein R² and R²⁰ together form a bivalent radicalof the formula —(CH₂)_(b)— wherein b is 3, 4 or 5, substituted with oneor two substituents that are halo, hydroxy, amino, mono- ordi(C₁₋₆alkyl)amino, C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl, orheteroaryl.
 16. The method of claim 10, where R² or R²⁰ are substitutedwith one or two substituents.
 17. The method of claim 10, where R²¹ orR²² are substituted with one or two substituents.
 18. The method ofclaim 10, wherein R²¹ and R²² together with the nitrogen to which theyare attached form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl,any of said groups are independently substituted with one or twosubstituents that are C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl, arylC₁₋₆alkyl, orheteroarylC₁₋₆alkyl.
 19. The method of claim 10, wherein R² and R²⁰together with the phenyl ring to which they are attached form anaphthalenyl group, substituted with one or two substituents eachindependently halo, hydroxy, amino, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl, or heteroaryl.
 20. Themethod of claim 10, wherein R² and R²⁰ together form a bivalent radicalof the formula —(CH₂)_(b)— wherein b is 3, 4 or 5, substituted with oneor two substituents that are halo, hydroxy, amino, mono- ordi(C₁₋₆alkyl)amino, C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, aryl, orheteroaryl.
 21. The method of claim 10, wherein the cancer is breastcancer, colorectal cancer, ovarian cancer, non-small cell lung cancer oracute myelogenous cancer.